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Cited by 52314-3-3 protein interactionsChemical Synthesis and AnalysisProtein Degradation and Inhibitors

Modulators of Protein–Protein Interactions

Open access
Milroy, Lech-Gustav, Grossmann, Tom N., Hennig, Sven, Brunsveld, Luc, Ottmann, Christian·2014·Chemical Reviews
DOI 10.1021/cr400698c
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Abstract

Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein-protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as 'undruggable' targets, the last two decades have seen an increasing number of successful examples of PPI modulators resulting in a growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This Perspective focuses on the hub protein 14-3-3, which has several hundred identified protein interaction partners and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide-mimetics and natural products.

AI snapshot

Written from the paper’s full text.

TL;DR

This perspective reviews the state of the art in modulating 14-3-3 protein–protein interactions (PPIs), a hub-protein family with several hundred binding partners, covering both inhibitors and stabilizers ranging from peptides and macrocycles to small molecules and natural products. It argues that stabilization ("molecular glue") is likely to offer better selectivity than inhibition, and that the field must look beyond the central phosphopeptide-binding groove.

Key findings

  • Inhibitors of 14-3-3 PPIs span peptide and small-molecule classes: the phage-display peptide R18 (1) was the first reported 14-3-3 PPI inhibitor; the ExoS-derived macrocyclic peptide βSS12 (2) bound 14-3-3ζ with a Kd of 41 nM versus 1.14 μM for the unmodified peptide (~30-fold improvement); and a Tau-epitope chimeric inhibitor (benzhydryl pyrrolidine C-terminus) bound with 3 orders of magnitude higher affinity than the unmodified phosphopeptide.
  • Small-molecule inhibitors include 2-5 (7) from small-molecule microarray screening (IC50 2.6–3.6 μM by FP), its phospho-serine mimetic prodrug 8 (IC50 5 μM against DG75 leukemia cell viability, with free phosphonate 9 inactive up to 100 μM), the Botta-series compounds BV01/BV02/BV101 and 13 (c-Abl nuclear translocation at 25 μM; sensitizes MDR cells to doxorubicin at 10 μM), FOBISIN101 (15; inhibits PRAS40 binding to 14-3-3ζ and 14-3-3γ with 9.3 and 16.4 μM potencies), and UTKO1 (17; IC50 1.98 μM for inhibiting cell migration, with 14-3-3ζ identified as the strongest-binding isoform).
  • Stabilizers are dominated by the fusicoccanes: fusicoccin A (21) acts as a "molecular glue" for 14-3-3 complexes; semisynthetic 23 gave a 20-fold stabilization of the 14-3-3/TASK3 interaction and, at 10 μM in Xenopus oocytes expressing human TASK3, a 45% increase in plasma-membrane TASK3 expression; C12-dehydroxy analogue 24 stabilized the 14-3-3–Gab2 PPI by a factor of 5.3; and fusicoccane–peptide hybrid 25 bound 14-3-3 with Kd 0.37 μM, stronger than a PMA2-derived phosphopeptide (Kd 1.24 μM).
  • Screening campaigns identified further stabilizers: a 37,000-compound screen yielded Epibestatin (28) and Pyrrolidone1 (29), later optimized to Pyrazole34 (30); a 58,019-compound screen against phospho-HSP20/14-3-3γ produced 268 modulators, with compound 85070 (14) showing up to 50 μM IC50; and AMP (31) was shown to act as a direct orthosteric stabilizer of the 14-3-3β/ChREBP interface.

Methods

  • This is a narrative perspective/review, not a primary experimental study; it synthesizes published structural, biophysical, and cellular work on 14-3-3 PPI modulation rather than reporting new data collection.
  • Evidence reviewed includes X-ray crystal structures of 14-3-3 in complex with partner peptides and larger protein constructs (e.g., AANAT, PMA2-CT52, Hd3a, HSPB6, ChREBP), fluorescence polarization and ELISA binding assays, NMR (NOESY/transfer NOE), SAXS, MALDI-MS/ESI-MS, virtual screening and docking, and cell-based assays (e.g., FOXO3a reporter, c-Abl translocation, airway smooth muscle contractility).
  • The paper organizes the literature by modulator class (inhibitors vs. stabilizers) and by chemical modality (peptides, macrocycles, small molecules, natural products, molecular tweezers).

Limitations

  • Stated by the paper: the molecular basis for 14-3-3's role in parasite pathogenicity is not well understood; the mechanism of action of HSP20 compound 85070 (14) and the basis of its functional effects are unknown; further work is needed to fully elucidate the diazene cleavage and covalent adduct formation observed for FOBISIN101 (15); and the great number of similar binding modes among 14-3-3 partners makes achieving specificity difficult, so groove-binding inhibitors risk side effects.
  • Stated by the paper: only a small percentage of the several hundred identified 14-3-3 PPIs has been investigated, and structural conclusions about distinct druggable pockets rest on a "somewhat limited set" of 14-3-3 crystal structures with larger domain partner proteins.
  • Evident from the text: as a perspective, it presents no systematic search strategy, inclusion criteria, or quantitative synthesis, so the selection of examples is illustrative rather than exhaustive; several reported potencies come from different assay formats and are not directly comparable.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1021/cr400698c

Cites

624 of 624 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 217 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Fragments from an NMR-based screen can bind to secondary binding sites outside the central phosphopeptide-accepting binding channel.

    “In this regard, we very recently found that fragments from an NMR-based screen can bind to secondary binding sites outside the central phosphopeptide-accepting binding channel. 164”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] (164) Sijbesma, E.; Skora, L.; Leysen, S.; Brunsveld, L.; Koch, U.; Nussbaumer, P.; Jahnke, W.; Ottmann, C. Identification of Two Secondary Ligand binding sites in 14-3-3 Proteins Using Fragment Screening. Biochemistry 2017 , 56 (30), 3972 -3982.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    14-3-3 proteins from T. spiralis play a crucial role in the early stages of the infection by maintaining the host-parasite relationship.

    “14-3-3 proteins from this parasite were shown to play a crucial role in the early stages of the infection by maintaining the host -parasite relationship. 79”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] (79) Yang, J.; Pan, W.; Sun, X.; Zhao, X.; Yuan, G.; Sun, Q.; Huang, J.; Zhu, X. Immunoproteomic Profile of Trichinella Spiralis Adult Worm Proteins Recognized by Early Infection Sera. Parasites Vectors 2015 , 8 (1), 20. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Interpretationreasoning

    14-3-3 proteins have substantial involvement in parasites' life cycles.

    “In summary, all these fi ndings demonstrate that 14-3-3 proteins have substantial involvement in parasites ' life cycles.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Active compounds against 14-3-3 alone will impact several binding partners and thus likely give rise to unwanted pharmacology.

    “The fact that 14-3-3 proteins serve purely as adapter proteins means that active compounds against 14-3-3 alone will impact several binding partners and thus likely give rise to unwanted pharmacology.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 14-3-3 proteins serve purely as adapter proteins.
  • Interpretationcitation

    If drugs target the complex formation between 14-3-3 and a protein partner, either by inhibition or stabilization, then intrinsic specificity should be possible.

    “However, if the drugs target the complex formation between 143-3 and a protein partner, either by inhibition or stabilization, then intrinsic speci fi city should be possible. 24”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] (24) Thiel, P.; Kaiser, M.; Ottmann, C. Small-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery? Angew. Chem., Int. Ed. 2012 , 51 (9), 2012 -2018. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. 18
  • May combine two claims. 65

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Each 14-3-3 monomer consists of nine alpha helices forming an amphipathic groove that can bind to (mostly phosphorylated) protein partners.

    “Each monomer consists of nine alpha helices forming an amphipathic groove that can bind to (mostly phosphorylated) protein partners (Figure 3). 46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] (46) Yaffe, M. B.; Rittinger, K.; Volinia, S.; Caron, P. R.; Aitken, A.; Leffers, H.; Gamblin, S. J.; Smerdon, S. J.; Cantley, L. C. The Structural Basis for 14-3-3:phosphopeptide Binding Specificity. Cell 1997 , 91 (7), 961 -971. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    14-3-3 proteins are eukaryotic adaptor proteins involved in many cellular processes such as cell-cycle control, signal transduction, protein trafficking, and apoptosis.

    “14-3-3 proteins are eukaryotic adaptor proteins involved in many cellular processes such as cell-cycle control, signal transduction, protein tra ffi cking, and apoptosis. 44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] (44) Hermeking, H.; Benzinger, A. 14-3-3 Proteins in Cell Cycle Regulation. Semin. Cancer Biol. 2006 , 16 (3), 183 -192. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    S. mansoni encodes four 14-3-3 isoforms that have roles in host immunity, parasite development, and survival.

    “This parasite encodes four 14-3-3 isoforms that have roles in host immunity, parasite development, and survival. 78”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] (78) McGonigle, S.; Pearce, E. J. 14-3-3 Proteins in Schistosoma Mansoni; Identification of a Second Epsilon Isoform. Int. J. Parasitol. 2002 , 32 (6), 685 -693. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    14-3-3 proteins from T. gondii induce hypermotility in infected host cells.

    “Moreover, it was demonstrated that, in this stage, 14-3-3 proteins from T. gondii induce hypermotility in infected host cells. 74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] (74) Weidner, J. M.; Kanatani, S.; Uchtenhagen, H.; Varas-Godoy, M.; Schulte, T.; Engelberg, K.; Gubbels, M. J.; Sun, H. S.; Harrison, R. E.; Achour, A.; Barragan, A. Migratory Activation of Parasitized Dendritic Cells by the Protozoan Toxoplasma Gondii 14-3-3 Protein. Cell. Microbiol. 2016 , 18 (11), 1537 -1550. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Most PDB entries of 14-3-3 crystal structures represent binary complexes of 14-3-3 with a peptide mimic of the phosphorylated binding site of the PPI partner protein.

    “Most PDB entries of 143-3 crystal structures represent binary complexes of 14-3-3 with a peptide mimic of the phosphorylated binding site of the PPI partner protein.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Stabilization of 14-3-3 PPIs is an especially promising approach because the problem of specificity might be solved more easily than with inhibitors.

    “In this context, stabilization of 14-3-3 PPIs is an especially promising approach because the problem of speci fi city might be solved more easily than with inhibitors.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The respective PPI interfaces of 14-3-3 complexes have relatively high variability.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ubiquity of 14-3-3 protein involvement in numerous human diseases has sparked interest in their use as novel targets for drug discovery.

    “In general, the ubiquity of 14-3-3 protein involvement in numerous human diseases has sparked interest in their use as novel targets for drug discovery. 44,49,65,86”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [44] (44) Hermeking, H.; Benzinger, A. 14-3-3 Proteins in Cell Cycle Regulation. Semin. Cancer Biol. 2006 , 16 (3), 183 -192. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [49] (49) Andrews, R. K.; Du, X.; Berndt, M. C. The 14-3-3zeta-GPIb-IX-V Complex as an Antiplatelet Target. Drug News Perspect. 2007 , 20 (5), 285 -292. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [65] (65) Berg, D.; Holzmann, C.; Riess, O. 14-3-3 Proteins in the Nervous System. Nat. Rev. Neurosci. 2003 , 4 (9), 752 -762. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [86] (86) Morrison, D. K. The 14-3-3 Proteins: Integrators of Diverse Signaling Cues That Impact Cell Fate and Cancer Development. Trends Cell Biol. 2009 , 19 (1), 16 -23. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    The mannitol pathway is missing in higher eukaryotes, representing an attractive target for the development of selective drugs.

    “From a drug discovery perspective, it is important to note that this pathway is missing in higher eukaryotes, thus representing an attractive target for the development of selective drugs. 68”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] (68) Siles-Lucas, M. D. M.; Gottstein, B. The 14-3-3 Protein: A Key Molecule in Parasites as in Other Organisms. Trends Parasitol. 2003 , 19 (12), 575 -581. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In Plasmodium berghei, host skeletal protein dematin is translocated from the erythrocyte membrane within the parasite, where it interacts with the Plasmodium 14-3-3, thus influencing the remodeling of the erythrocytic cytoskeleton and modulating host erythrocyte invasion.

    “In Plasmodium berghei , the host skeletal protein dematin is translocated from the erythrocyte membrane within the parasite, where it interacts with the Plasmodium 14-3-3, thus in fl uencing the remodeling of the erythrocytic cytoskeleton and modulating the host erythrocyte invasion. 70”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] (70) Lalle, M.; Curra ̀ , C.; Ciccarone, F.; Pace, T.; Cecchetti, S.; Fantozzi, L.; Ay, B.; Breton, C. B.; Ponzi, M. Dematin, a Component of the Erythrocyte Membrane Skeleton, Is Internalized by the Malaria Parasite and Associates with Plasmodium 14-3-3. J. Biol. Chem. 2011 , 286 (2), 1227 -1236. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In E. multilocularis, 14-3-3 proteins are implicated in the tumor-like growth process.

    “In E. multilocularis , 14-3-3 proteins have been reported to be implicated in the tumor-like growth process. 76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] (76) Siles-Lucas, M.; Felleisen, R. S. J.; Hemphill, A.; Wilson, W.; Gottstein, B. Stage-Specific Expression of the 14-3-3 Gene in Echinococcus Multilocularis. Mol. Biochem. Parasitol. 1998 , 91 (2), 281 -293. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mode III motifs were later defined as C-terminal sequences, where the phosphorylated serine or threonine is the penultimate residue of the binding partner.

    “Mode III motifs were later de fi ned as C-terminal sequences, where the phosphorylated serine or threonine is the penultimate residue of the binding partner. 87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] (87) Coblitz, B.; Wu, M.; Shikano, S.; Li, M. C-Terminal Binding: An Expanded Repertoire and Function of 14-3-3 Proteins. FEBS Lett. 2006 , 580 (6), 1531 -1535. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Binding of Cp14b to its own C-terminus is much stronger when the C-terminus is truncated, suggesting competition between C-terminus and its phosphorylated mimic.

    “This binding is much stronger when the C-terminus is truncated, thus suggesting a competition between C-terminus and its phosphorylated mimic. 80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] (80) Brokx, S. J.; Wernimont, A. K.; Dong, A.; Wasney, G. A.; Lin, Y. H.; Lew, J.; Vedadi, M.; Lee, W. H.; Hui, R. Characterization of 14-3-3 Proteins from Cryptosporidium Parvum. PLoS One 2011 , 6 (8), e14827. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisenone given

    A second reason is that the 14-3-3 binding sequences are prevalently localized in disordered regions of their target proteins and only undergo a disorder-to-order transition when binding to 14-3-3.

    “A second reason is that the 14-3-3 binding sequences are prevalently localized in disordered regions of their target proteins and only undergo a disorder-to-order transition when binding to 14-3-3.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    14-3-3 proteins have been associated with the development of neurodegenerative diseases and virulence of human pathogenic organisms.

    “In addition to their participation in diverse cancers, 44 they have been associated with the development of neurodegenerative diseases 65 and virulence of human pathogenic organisms. 66,67”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [44] (44) Hermeking, H.; Benzinger, A. 14-3-3 Proteins in Cell Cycle Regulation. Semin. Cancer Biol. 2006 , 16 (3), 183 -192. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [65] (65) Berg, D.; Holzmann, C.; Riess, O. 14-3-3 Proteins in the Nervous System. Nat. Rev. Neurosci. 2003 , 4 (9), 752 -762. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [66] (66) Fu, H.; Coburn, J.; Collier, R. J. The Eukaryotic Host Factor That Activates Exoenzyme S of Pseudomonas Aeruginosa Is a Member of the 14-3-3 Protein Family. Proc. Natl. Acad. Sci. U. S. A. 1993 , 90 (6), 2320 -2324. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [67] (67) Ottmann, C.; Yasmin, L.; Weyand, M.; Veesenmeyer, J. L.; Diaz, M. H.; Palmer, R. H.; Francis, M. S.; Hauser, A. R.; Wittinghofer, A.; Hallberg, B. Phosphorylation-Independent Interaction between 14-3-3 and Exoenzyme S: From Structure to Pathogenesis. EMBO J. 2007 , 26 (3), 902 -913. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mode I and II interaction partners were defined to require an arginine at position -3 with respect to the phosphorylated serine or threonine residue and a proline residue at position +2.

    “Mode I and II interaction partners were de fi ned to require an arginine at position -3 with respect to the phosphorylated serine or threonine residue and a proline residue at position +2 (more speci fi cally; (I) RSX(pS/ T)XP or (II) RX(F/Y)X(pS)XP). 46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] (46) Yaffe, M. B.; Rittinger, K.; Volinia, S.; Caron, P. R.; Aitken, A.; Leffers, H.; Gamblin, S. J.; Smerdon, S. J.; Cantley, L. C. The Structural Basis for 14-3-3:phosphopeptide Binding Specificity. Cell 1997 , 91 (7), 961 -971. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premiseown data

    In the crystal structure, the entire construct of Hd3a (residues 6-170) is visible, making it the second-largest 14-3-3 partner protein after AANAT (residues 18-196) that has been cocrystallized with 14-3-3.

    “In the crystal structure, the entire construct of Hd3a (residues 6 -170) is visible, making it the second-largest 14-3-3 partner protein after AANAT (residues 18 -196) that has been cocrystallized with 14-3-3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The 14-3-3/HSPB6 interaction surface spans ∼400 Å2 and contains an essential salt bridge between Arg224 (14-3-3) and Glu86 (HSPB6).

    “The interaction surface spans ∼ 400 Å 2 and contains an essential salt bridge between Arg224 (14-3-3) and Glu86 (HSPB6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] (56) Sluchanko, N. N.; Beelen, S.; Kulikova, A. A.; Weeks, S. D.; Antson, A. A.; Gusev, N. B.; Strelkov, S. V. Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator. Structure 2017 , 25 (2), 305 -316. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    The C-terminal 30 amino acid residues of PMA2-CT52 bind as an elongated peptide and a short helix in the amphipathic groove of each 14-3-3 monomer, whereas the N-terminal 22 amino acid residues form a helix that perpendicularly leaves the 14-3-3 binding channel.

    “The C-terminal 30 amino acid residues bind as an elongated peptide and a short helix in the amphipathic groove of each 14-3-3 monomer, whereas the Nterminal 22 amino acid residues of PMA2-CT52 form a helix that perpendicularly leaves the 14-3-3 binding channel.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    Two Hd3a molecules bind to one 14-3-3 dimer and occupy an unusual position that is not part of the central binding channel as seen with all other 14-3-3 ligands including AANAT.

    “Two Hd3a molecules bind to one 143-3 dimer and occupy an unusual position that is not part of the central binding channel as seen with all other 14-3-3 ligands including AANAT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Peptide R18 (1), a 20-amino-acid peptide, was the first reported 14-3-3 PPI inhibitor and was identified from phage display by the Fu Laboratory.

    “The fi rst reported 14-3-3 PPI inhibitor, peptide R18 ( 1 ) (20 amino acid residues), was identi fi ed from a phage display by the Fu Laboratory. 111”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] (111) Wang, B.; Yang, H.; Liu, Y. C.; Jelinek, T.; Zhang, L.; Ruoslahti, E.; Fu, H. Isolation of High-Affinity Peptide Antagonists of 14-3-3 Proteins by Phage Display. Biochemistry 1999 , 38 (38), 12499 -12504. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    This activation is strongly increased by the natural product fusicoccin, which fills a gap in the interface of 14-3-3 with the regulatory C-terminus of PMA.

    “This activation is strongly increased by the natural product fusicoccin, 100,101 which fi lls a gap in the interface of 14-3-3 with the regulatory C-terminus (CT) of PMA. 102,103”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [100] (100) Olsson, A.; Svennelid, F.; Ek, B.; Sommarin, M.; Larsson, C. A. Phosphothreonine Residue at the C-Terminal End of the Plasma Membrane H + -ATPase Is Protected by Fusicoccin-Induced 14-3-3 Binding. Plant Physiol. 1998 , 118 (2), 551 -555. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [101] (101) Svennelid, F.; Olsson, A.; Piotrowski, M.; Rosenquist, M.; Ottman, C.; Larsson, C.; Oecking, C.; Sommarin, M. Phosphorylation of Thr-948 at the C Terminus of the Plasma Membrane H(+)-ATPase Creates a Binding Site for the Regulatory 14-3-3 Protein. Plant Cell 1999 , 11 (12), 2379 -2391. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [102] (102) Wu ̈ rtele, M.; Jelich-Ottmann, C.; Wittinghofer, A.; Oecking, C. Structural View of a Fungal Toxin Acting on a 14-3-3 Regulatory Complex. EMBO J. 2003 , 22 (5), 987 -994. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [103] (103) Ottmann, C.; Marco, S.; Jaspert, N.; Marcon, C.; Schauer, N.; Weyand, M.; Vandermeeren, C.; Duby, G.; Boutry, M.; Wittinghofer, A.; Rigaud, J.-L.; Oecking, C. Structure of a 14-3-3 Coordinated Hexamer of the Plant Plasma Membrane H+-ATPase by Combining X-Ray Crystallography and Electron Cryomicroscopy. Mol. Cell 2007 , 25 (3), 427 -440. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Because all structurally characterized 14-3-3 binding motifs adopt irregular and extended conformations within the 14-3-3 ligand-binding grooves, the macrocyclization approach should be applicable to the majority of 14-3-3 binding interactions.

    “Because all 14-3-3 binding motifs structurally characterized so far adopt irregular and extended conformations within the 14-3-3 ligand-binding grooves, this approach should be applicable to the majority of 14-3-3 binding interactions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] (115) Glas, A.; Bier, D.; Hahne, G.; Rademacher, C.; Ottmann, C.; Grossmann, T. N. Constrained Peptides with Target-Adapted CrossLinks as Inhibitors of a Pathogenic Protein-Protein Interaction. Angew. Chem., Int. Ed. 2014 , 53 (9), 2489 -2493. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In early 2017, Sluchanko, Strelkov, and co-workers reported a 14-3-3 assembly with the full-length HSPB6 dimer.

    “In early 2017, Sluchanko, Strelkov, and co-workers reported a 14-3-3 assembly with the full-length HSPB6 dimer (Figure 5). 56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] (56) Sluchanko, N. N.; Beelen, S.; Kulikova, A. A.; Weeks, S. D.; Antson, A. A.; Gusev, N. B.; Strelkov, S. V. Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator. Structure 2017 , 25 (2), 305 -316. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The crystal structure of ExoS-derived peptide H (3) was obtained by ring-closing alkyne metathesis, used for the first time for stabilization of an irregular peptide secondary structure.

    “Figure 7D shows the crystal structure of an ExoS-derived peptide H ( 3 ), which has been obtained by a ring-closing alkyne metathesis used here for the fi rst time for the stabilization of an irregular peptide secondary structure. 116”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] (116) Cromm, P. M.; Wallraven, K.; Glas, A.; Bier, D.; Fu ̈ rstner, A.; Ottmann, C.; Grossmann, T. N. Constraining an Irregular Peptide Secondary Structure through Ring-Closing Alkyne Metathesis. ChemBioChem 2016 , 17 (20), 1915 -1919. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The R18/14-3-3 structure revealed salt-bridge interactions between the glutamic acid side-chain carboxyl group and three arginines of 14-3-3, plus an extensive hydrophobic contact surface between the two leucine residues of 1 and a number of 14-3-3 residues.

    “This structure revealed that, in addition to salt-bridge interactions between the carboxyl group of the glutamic acid side chain and three arginines of 14-33, there is an extensive hydrophobic contact surface between the two leucine residues of 1 and a number of 14-3-3 residues (Figure 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] (112) Petosa, C.; Masters, S. C.; Bankston, L. A.; Pohl, J.; Wang, B.; Fu, H.; Liddington, R. C. 14-3-3 ζ Binds a Phosphorylated Raf Peptide and an Unphosphorylated Peptide via Its Conserved Amphiphatic Groove. J. Biol. Chem. 1998 , 273 (26), 16305 -16310. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HSPB6 (HSP20) is involved in smooth muscle relaxation and cardioprotection and is a binding partner for 14-3-3 upon phosphorylation of Ser16.

    “HSPB6 (also known as HSP20) is involved in smooth muscle relaxation and cardio protection and was identi fi ed as a binding partner for 14-3-3 upon phosphorylation of Ser16. 109,110”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] (109) Bakthisaran, R.; Tangirala, R.; Rao, C. M. Small Heat Shock Proteins: Role in Cellular Functions and Pathology. Biochim. Biophys. Acta, Proteins Proteomics 2015 , 1854 (4), 291 -319. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [110] (110) Chernik, I. S.; Seit-Nebi, A. S.; Marston, S. B.; Gusev, N. B. Small Heat Shock Protein Hsp20 (HspB6) as a Partner of 14-3-3gamma. Mol. Cell. Biochem. 2007 , 295 (1 -2), 9 -17. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Expression of a longer 64-amino-acid peptide with two R18-like inhibiting sequences resulted in apoptosis, sensitized cancer cells to cisplatin, and suppressed tumor growth in mice.

    “In later studies, Fu et al. showed that expression of a longer peptide of 64 amino acid residues with two such inhibiting sequences resulted in apoptosis, sensitized cancer cells for the antineoplastic drug cisplatin, and suppressed tumor growth in mice. 113,114”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [113] (113) Masters, S. C.; Fu, H. 14-3-3 Proteins Mediate an Essential AntiApoptotic Signal. J. Biol. Chem. 2001 , 276 (48), 45193 -45200. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [114] (114) Cao, W.; Yang, X.; Zhou, J.; Teng, Z.; Cao, L.; Zhang, X.; Fei, Z. Targeting 14-3-3 Protein, Difopein Induces Apoptosis of Human Glioma Cells and Suppresses Tumor Growth in Mice. Apoptosis 2010 , 15 (2), 230 -241. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    By fully sequestering 14-3-3 binding sites, HSPB6 blocks interactions with other partner proteins, acting as a phospho-switching 14-3-3 regulator.

    “The authors state that by fully sequestering 14-3-3 binding sites, the chaperone HSPB6 blocks interactions with other partner proteins, thus acting as a phospho-switching 14-3-3 regulator.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] (56) Sluchanko, N. N.; Beelen, S.; Kulikova, A. A.; Weeks, S. D.; Antson, A. A.; Gusev, N. B.; Strelkov, S. V. Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator. Structure 2017 , 25 (2), 305 -316. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Direct interaction between 13 and recombinant 14-3-3σ was demonstrated by NOESY experiments, corroborating the mechanism of action of 13 at the molecular level.

    “The direct interaction between 13 and recombinant 14-3-3 σ was demonstrated by NOESY experiments, thus corroborating the mechanism of action of 13 at the molecular level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] (128) Valensin, D.; Cau, Y.; Calandro, P.; Vignaroli, G.; Dello Iacono, L.; Chiariello, M.; Mori, M.; Botta, M. Molecular Insights to the Bioactive Form of BV02, a Reference Inhibitor of 14-3-3 σ ProteinProtein Interactions. Bioorg. Med. Chem. Lett. 2016 , 26 (3), 894 -898. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    In the presence of 14-3-3σ, conversion of 13 back into 12 is slowed down, indicating that temperature and pH are not the only variables influencing interconversion.

    “Indeed, in the presence of 14-3-3 σ , the conversion of 13 back into 12 was slowed down, indicating that temperature and pH are not the only variables that in fl uence the compounds interconversion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] (128) Valensin, D.; Cau, Y.; Calandro, P.; Vignaroli, G.; Dello Iacono, L.; Chiariello, M.; Mori, M.; Botta, M. Molecular Insights to the Bioactive Form of BV02, a Reference Inhibitor of 14-3-3 σ ProteinProtein Interactions. Bioorg. Med. Chem. Lett. 2016 , 26 (3), 894 -898. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Upon cell entry, the nitrofurfuryl group of prodrug 8 is cleaved off by enzymatic reduction and spontaneous expulsion to deliver a phosphoamidate anion; subsequent intracellular cyclization and spontaneous hydrolysis yields the biologically active phosphonate product 19a (9).

    “Upon entry into the cell, the nitrofurfuryl group was cleaved o ff by enzymatic reduction and spontaneous expulsion to deliver a phosphoamidate anion. Subsequent intracellular cyclization of an intermediate followed by spontaneous hydrolysis yields the biologically active phosphonate product 19a ( 9 ). 123”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] (123) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity. Chem. Biol. 2012 , 19 (6), 764 -771. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Active metabolite 9 inhibited the interaction between immobilized 14-3-3τ and phosphorylated FOXO3a at physiologically relevant concentrations in lysates of DG75 leukemia cells transfected with FOXO3a and Akt1, whereas prodrug 8 was inactive.

    “Active metabolite 9 was able to inhibit the interaction between immobilized 14-3-3 τ and phosphorylated FOXO3a at physiologically relevant concentrations in lysates of DG75 leukemia cells transfected with FOXO3a and Akt1, whereas prodrug 8 was inactive.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] (123) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity. Chem. Biol. 2012 , 19 (6), 764 -771. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: FOXO3A is a Forkhead-family transcription factor inactivated by Akt1 phosphorylation and subsequent 14-3-3 binding.

  • May combine two claims.

    Interpretationcitation

    Extending the C-terminus of the Tau phosphopeptide with a hydrophobic group to target the conserved hydrophobic pocket within the amphiphilic groove of 14-3-3 was suggested to improve its poor binding affinity, leading to modified peptides 109B (4), 126B (5), and 201D (6).

    “This suggested that the poor binding a ffi nity of this phosphopeptide for 14-3-3 could be improved by extending its C-terminus with a hydrophobic group to target the highly conserved hydrophobic pocket within the amphiphilic groove of 14-3-3, which led to 143-3 inhibiting modi fi ed peptides 109B ( 4 ), 126B ( 5 ), and 201D ( 6 ) (Figure 8B -D). 121”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] (121) Milroy, L. G.; Bartel, M.; Henen, M. A.; Leysen, S.; Adriaans, J. M. C.; Brunsveld, L.; Landrieu, I.; Ottmann, C. Stabilizer-Guided Inhibition of Protein-Protein Interactions. Angew. Chem., Int. Ed. 2015 , 54 (52), 15720 -15724. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 9 (13), a phthalimide derivative of 12, promotes c-Abl nuclear translocation and sensitizes multidrug-resistant cancer stem cells.

    “In 2014, the same group published the discovery of compound 9 ( 13 , Figure 9C), a phthalimide derivative of 12 that is able to promote c-Abl nuclear translocation as well as to sensitize multidrug-resistant (MDR) cancer stem cells. 127”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] (127) Mori, M.; Vignaroli, G.; Cau, Y.; Dinic ̈ , J.; Hill, R.; Rossi, M.; Colecchia, D.; Pes ̌ ic ̈ , M.; Link, W.; Chiariello, M.; Ottmann, C.; Botta, M. Discovery of 14-3-3 Protein-Protein Interaction Inhibitors That Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693. ChemMedChem 2014 , 9 (5), 973 -983. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 15 was initially reported in 1998 as the P2X receptor antagonist MRS-2159 and was identified by screening the Sigma-Aldrich LOPAC library in a FP-based binding assay based on 14-3-3γ and a phosphorylated Raf-1 peptide.

    “Compound 15 (Figure 10A), initially reported in 1998 as the P2X receptor antagonist MRS-2159, 131 was identi fi ed by screening of the Sigma-Aldrich LOPAC library in a FP-based binding assay based on 14-3-3 γ and a phosphorylated Raf-1 peptide.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [131] (131) Kim, Y.-C.; Camaioni, E.; Ziganshin, A. U.; Ji, X.-D.; King, B. F.; Wildman, S. S.; Rychkov, A.; Yoburn, J.; Kim, H.; Mohanram, A.; Harden, T. K.; Boyer, J. L.; Burnstock, G.; Jacobson, K. A. Synthesis and Structure-Activity Relationships of Pyridoxal-6-Arylazo-5 ′ -phosphate and Phosphonate Derivatives as P2 Receptor Antagonists. Drug Dev. Res. 1998 , 45 (2), 52 -66. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 15 is a pan-14-3-3 inhibitor and inhibited binding of PRAS40 to 14-3-3ζ and 14-3-3γ with similar potencies (9.3 and 16.4 μM, respectively).

    “Compound 15 was shown to be a pan-14-3-3 inhibitor and inhibited the binding of PRAS40 to 14-3-3 ζ and 14-3-3 γ with similar potencies (9.3 and 16.4 μ M, respectively).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Five hits from the small-molecule microarray had Kd values between 0.6 and 1.03 μM, of which three featured substitution of the N-terminal peptide part and two of the C-terminal peptide part.

    “Five hits were found with K d values between 0.6 and 1.03 μ M, of which three featured a substitution of the N-terminal peptide part and two of the C-terminal peptide part.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] (122) Wu, H.; Ge, J.; Yao, S. Q. Microarray-Assisted High-Throughput Identification of a Cell-Permeable Small-Molecule Binder of 14-3-3 Proteins. Angew. Chem., Int. Ed. 2010 , 49 (37), 6528 -6532. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Repressed FOXO3a activity was recovered dose-dependently by addition of compound 8, concordant with reduced retention of phosphorylated FOXO3a by 14-3-3 in the cytoplasm.

    “The repressed FOXO3a activity was recovered in a dosedependent manner by addition of compound 8 in concordance with reduced retention of phosphorylated FOXO3a by 14-3-3 in the cytoplasm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] (123) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity. Chem. Biol. 2012 , 19 (6), 764 -771. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: FOXO3A is a Forkhead-family transcription factor inactivated by Akt1 phosphorylation and subsequent 14-3-3 binding.

  • May combine two claims.

    Premisecitation

    Molecule 13 promotes c-Abl nuclear translocation at 25 μM and decreases the IC50 of doxorubicin by increasing its accumulation in MDR cancer cells at 10 μM.

    “Most notably, molecule 13 was found to promote c-Abl nuclear translocation at 25 μ Mand has been shown to decrease the IC 50 of doxorubicin by increasing its accumulation in MDR cancer cells at 10 μ Mconcentration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] (127) Mori, M.; Vignaroli, G.; Cau, Y.; Dinic ̈ , J.; Hill, R.; Rossi, M.; Colecchia, D.; Pes ̌ ic ̈ , M.; Link, W.; Chiariello, M.; Ottmann, C.; Botta, M. Discovery of 14-3-3 Protein-Protein Interaction Inhibitors That Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693. ChemMedChem 2014 , 9 (5), 973 -983. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 12 inhibited the 14-3-3/c-Abl interaction and promoted c-Abl nuclear translocation at low micromolar concentration in Ba/F3 cells expressing wild-type Bcr-Abl and its Imatinib-resistant T315I mutation.

    “Indeed, 12 was able to inhibit 14-3-3/c-Abl interaction and promote c-Abl nuclear translocation at low micromolar concentration in Ba/F3 cells expressing the wild-type Bcr-Abl as well as its Imatinib-resistant T315I mutation. 125”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] (125) Mancini, M.; Corradi, V.; Petta, S.; Barbieri, E.; Manetti, F.; Botta, M.; Santucci, M. A. A New Nonpeptidic Inhibitor of 14-3-3 Induces Apoptotic Cell Death in Chronic Myeloid Leukemia Sensitive or Resistant to Imatinib. J. Pharmacol. Exp. Ther. 2011 , 336 (3), 596 -604. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Compound 14 was the most efficient in causing, in a dose-dependent manner, a decrease in cell stiffness, a decrease in contractile force in ASM cells, and an attenuation of active force development of intact tissue ex vivo.

    “Compound 14 was the most e ffi cient in causing, in a dose-dependent manner, a decrease in cell sti ff ness, decrease in contractile force in ASM cells, and an attenuation of active force development of intact tissue ex vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] (129) An, S. S.; Askovich, P. S.; Zarembinski, T. I.; Ahn, K.; Peltier, J. M.; von Rechenberg, M.; Sahasrabudhe, S.; Fredberg, J. J. A Novel Small Molecule Target in Human Airway Smooth Muscle for Potential Treatment of Obstructive Lung Diseases: A Staged High-Throughput Biophysical Screening. Respir. Res. 2011 , 12 (1), 8. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 13 is the product of spontaneous dehydration of 12 under aqueous conditions and is the bioactive form of 12.

    “Subsequently, it was discovered that 13 was the product of spontaneous dehydration of 12 under aqueous conditions (Figure 9C) and was, in fact, the bioactive form of 12, as shown by a detailed NMR spectroscopy study. 128”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] (128) Valensin, D.; Cau, Y.; Calandro, P.; Vignaroli, G.; Dello Iacono, L.; Chiariello, M.; Mori, M.; Botta, M. Molecular Insights to the Bioactive Form of BV02, a Reference Inhibitor of 14-3-3 σ ProteinProtein Interactions. Bioorg. Med. Chem. Lett. 2016 , 26 (3), 894 -898. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Compound 15 inhibited 14-3-3-dependent activation of nonphosphorylated 14-3-3 client protein ExoS in a functional assay, suggesting that 15 inhibits binding of both phosphorylated and nonphosphorylated client proteins.

    “Compound 15 also inhibited the 14-3-3-dependent activation of nonphosphorylated 14-3-3 client protein ExoS in a functional assay, suggesting that 15 inhibits the binding of both phosphorylated and nonphosphorylated client proteins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 8 inhibits viability of DG75 leukemia cells with an IC50 of 5 μM and induces apoptosis in the same concentration range, whereas free phosphonate 9 does not show significant inhibition at concentrations up to 100 μM.

    “Compound 8 inhibits viability of DG75 leukemia cells with an IC50 value of 5 μ M and induces apoptosis in the same concentration range, whereas free phosphonate 9 does not show any signi fi cant inhibition at concentrations up to 100 μ M.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] (123) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity. Chem. Biol. 2012 , 19 (6), 764 -771. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    BV01 (10) and BV101 (11) were additional 14-3-3 PPI inhibitors initially discovered by an in silico approach and promoted c-Abl nuclear translocation in Ba/F3 cells expressing WT and Imatinib-resistant T315I-mutated Bcr-Abl constructs.

    “These molecules, namely BV01 ( 10 ) and BV101 ( 11 ) (Figure 9C), were also initially discovered by an in silico approach, 126 and promoted c-Abl nuclear translocation in Ba/F3 cells expressing the WT and the Imatinib-resistant T315I-mutated Bcr-Abl constructs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] (126) Corradi, V.; Mancini, M.; Santucci, M. A.; Carlomagno, T.; Sanfelice, D.; Mori, M.; Vignaroli, G.; Falchi, F.; Manetti, F.; Radi, M.; Botta, M. Computational Techniques Are Valuable Tools for the Discovery of Protein-Protein Interaction Inhibitors: The 14-3-3 σ Case. Bioorg. Med. Chem. Lett. 2011 , 21 (22), 6867 -6871. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    siRNA silencing of 14-3-3ζ suppressed lamellopodia formation in a tumor cell line, increasing confidence that the observed effect of 17 is due to binding to 14-3-3ζ.

    “siRNA silencing of 14-3-3 ζ led to suppression of lamellopodia formation (which is key to cell migration) in a tumor cell line thus increasing con fi dence that the observed e ff ect of 17 is due to binding to 14-3-3 ζ .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [137] (137) Tashiro, E.; Imoto, M. Screening and Target Identification of Bioactive Compounds That Modulate Cell Migration and Autophagy. Bioorg. Med. Chem. 2016 , 24 (15), 3283 -3290. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Natural Moverastin is produced as a diastereomeric mixture of secondary alcohols, and separation led to isolation of pure diastereoisomers Moverastin A (16A) and B (16B).

    “Natural Moverastin is produced as a diastereomeric mixture of secondary alcohols, and separation led to the isolation of the pure diastereoisomers Moverastin A ( 16A ) and B ( 16B ) (Figure 11). 134”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    siRNA knockdown experiments showed only Tiam1 to have an effect on cell migration, and inhibition of binding of Tiam1 to 14-3-3ζ by 17 was confirmed both in cell lysates and cultured cells.

    “siRNA knockdown experiments showed only Tiam1 to have an e ff ect on cell migration and inhibition of the binding of Tiam1 to 14-3-3 ζ by 17 was con fi rmed both in cell lysates and cultured cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    All seven mammalian 14-3-3 isoforms were tested for binding to 17, and 14-3-3ζ was confirmed as the isoform with the strongest binding affinity.

    “All seven mammalian 14-3-3 isoforms were then tested for binding to 17 , and 14-3-3 ζ was con fi rmed as the isoform with the strongest binding a ffi nity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [137] (137) Tashiro, E.; Imoto, M. Screening and Target Identification of Bioactive Compounds That Modulate Cell Migration and Autophagy. Bioorg. Med. Chem. 2016 , 24 (15), 3283 -3290. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Inhibition of FT leads to a reduction of HRAS farnesylation and inhibition of membrane localization, subsequently leading to a reduction in cell migration and tumor metastasis.

    “Inhibition of FT therefore leads to a reduction of HRAS farnesylation and inhibition of membrane localization, subsequently leading to a reduction in cell migration and tumor metastasis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HRas is a common human oncogene, and HRAS protein plays a key role in cancer cell migration.
    • Rests on an assumption: HRAS activity is dependent on posttranslational prenylation (farnesylation) by FT, which leads to activation of HRAS by membrane localization.

  • May combine two claims.

    Premiseown data

    MALDI-MS showed that X-ray exposure was required for formation of the covalent adduct, as only irradiated samples exhibited a 183 Da increase in molecular weight corresponding to the 15 fragment observed in the crystal structure.

    “MALDI-MS also showed that X-ray exposure was required for formation of this covalent adduct as only irradiated samples exhibited the 183 Da increase in molecular weight corresponding to the 15 fragment observed in the crystal structure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Compounds 15A and 15B exhibited almost complete loss of potency, indicating that the phosphate and phenyldiazene moieties are required for binding to 14-3-3ζ.

    “Compounds 15A and 15B (Figure 10A) both exhibited almost complete loss of potency, indicating that the phosphate and phenyldiazene moieties were required for binding to 14-3-3 ζ .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Coprecipitation experiments with biotinylated UTKO1 derivative 18 and unlabeled 17 identified two 14-3-3 isoforms (ε and ζ) as potential 17-binding proteins, of which 14-3-3ζ was considered the most likely candidate for biological activity due to previous reports of its involvement in cell migration.

    “Coprecipitation experiments with 18 and unlabeled 17 identi fi ed two 14-3-3 isoforms ( ε and ζ ) as potential 17 -binding proteins of which 14-3-3 ζ was considered to be the most likely candidate for the biological activity due to previous reports of its involvement in cell migration.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [137] (137) Tashiro, E.; Imoto, M. Screening and Target Identification of Bioactive Compounds That Modulate Cell Migration and Autophagy. Bioorg. Med. Chem. 2016 , 24 (15), 3283 -3290. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The C-terminal domain is the most variable region within the 14-3-3 family, and this was proposed as an explanation for the selective binding of 17 to 14-3-3ζ.

    “This C-terminal domain is the most variable region within the 14-3-3 family, and this was proposed as an explanation for the selective binding of 17 to 14-3-3 ζ .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [137] (137) Tashiro, E.; Imoto, M. Screening and Target Identification of Bioactive Compounds That Modulate Cell Migration and Autophagy. Bioorg. Med. Chem. 2016 , 24 (15), 3283 -3290. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compounds 16A and 16B inhibit FT in vitro with similar potency and decrease nuclear localization of Ras in a tumor cell line.

    “Compounds 16A and 16B were shown to inhibit FT in vitro with similar potency and also shown to decrease the nuclear localization of Ras in a tumor cell line. 134”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    A structure of 15 with 14-3-3σ also exhibited imine formation with the aldehyde and an intact diazene moiety, but electron density indicated a high degree of ligand flexibility in this region compared with the hydrazine adduct observed by Fu et al.

    “They then obtained a structure of 15 with 14-3-3 σ , which in their hands also exhibited imine formation with the aldehyde. It also exhibited with an intact diazene moiety; however, the electron density indicated a high degree of ligand fl exibility in this region when compared with the hydrazine adduct observed by Fu et al.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] (132) Ro ̈ glin, L.; Thiel, P.; Kohlbacher, O.; Ottmann, C. Covalent Attachment of Pyridoxal-Phosphate Derivatives to 14-3-3 Proteins. Proc. 18. Natl. Acad. Sci. U. S. A. 2012 , 109 (18), E1051 -3 author reply E1054.. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Neither the stability nor cellular localization of Tiam1 was affected by 17, suggesting that a conformational change upon binding to 14-3-3ζ is required for activation of Tiam1 and that this is inhibited by 17.

    “Interestingly, neither the stability nor cellular localization of Tiam1 was a ff ected by 17 , suggesting that a conformational change upon binding to 14-3-3 ζ is required for activation of Tiam1 and that this is inhibited by 17 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] (134) Takemoto, Y.; Watanabe, H.; Uchida, K.; Matsumura, K.; Nakae, K.; Tashiro, E.; Shindo, K.; Kitahara, T.; Imoto, M. Chemistry and Biology of Moverastins, Inhibitors of Cancer Cell Migration, Produced by Aspergillus. Chem. Biol. 2005 , 12 (12), 1337 -1347. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    X-ray activation is not required for 15 to bind to 14-3-3ζ, as it inhibited binding of a Raf-1 peptide to 14-3-3ζ in an ELISA-based assay.

    “However, Xray activation is not required for 15 to bind to 14-3-3 ζ , as it was able to inhibit binding of a Raf-1 peptide to 14-3-3 ζ in an ELISAbased assay.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] (130) Zhao, J.; Du, Y.; Horton, J. R. R.; Upadhyay, A. K. K.; Lou, B.; Bai, Y.; Zhang, X.; Du, L.; Li, M.; Wang, B.; et al. Discovery and Structural Characterization of a Small Molecule 14-3-3 Protein-Protein Interaction Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 (39), 16212 -16216. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Leu174 and Val178 in contact with the phosphate-accommodating moiety contribute large van der Waals energies, and Leu126 provides large electrostatic energies.

    “In addition, two residues (Leu174 and Val178) in contact with a moiety accommodating the phosphate group contribute large van der Waals energies, and residue Leu126 provides large electrostatic energies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] (139) Hu, G.; Cao, Z.; Xu, S.; Wang, W.; Wang, J. Revealing the Binding Modes and the Unbinding of 14-3-3 σ Proteins and Inhibitors by Computational Methods. Sci. Rep. 2015 , 5 , 16481. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Although the physiological potency is relatively weak, 21 stabilizes the 14-3-3 interaction with CFTR, thus promoting trafficking of CFTR to the plasma membrane.

    “Although the physiological potency is relatively weak, 21 has recently been shown to stabilize the 14-3-3 interaction with the cystic fi brosis transmembrane conductance regulator (CFTR), thus promoting tra ffi cking of CFTR to the plasma membrane. 55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] (55) Stevers, L. M.; Lam, C. V.; Leysen, S. F. R.; Meijer, F. A.; van Scheppingen, D. S.; de Vries, R. M. J. M.; Carlile, G. W.; Milroy, L. G.; Thomas, D. Y.; Brunsveld, L.; Ottmann, C. Characterization and SmallMolecule Stabilization of the Multisite Tandem Binding between 14-3-3 and the R Domain of CFTR. Proc. Natl. Acad. Sci. U. S. A. 2016 , 113 (9), E1152 -E1161. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bier et al. published in 2013 another class of phosphate-containing inhibitors called molecular tweezers.

    “Bier et al. published in 2013 another class of phosphate-containing inhibitors called molecular tweezers (Figure 13A and B). 140”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] (140) Bier, D.; Rose, R.; Bravo-Rodriguez, K.; Bartel, M.; RamirezAnguita, J. M.; Dutt, S.; Wilch, C.; Kla ̈ rner, F.-G.; Sanchez-Garcia, E.; Schrader, T.; Ottmann, C. Molecular Tweezers Modulate 14-3-3 Protein-Protein Interactions. Nat. Chem. 2013 , 5 (3), 234 -239. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    By binding to Lys214, the molecular tweezer can interfere with the function of 14-3-3 as an adapter protein, inhibiting binding of phosphorylated C-Raf and unphosphorylated ExoS to 14-3-3σ.

    “By binding to this position, it can interfere with the function of 14-3-3 as an adapter protein, inhibiting, for example, the binding of phosphorylated C-Raf and unphosphorylated ExoS (Figure 13) to 14-3-3 σ .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] (140) Bier, D.; Rose, R.; Bravo-Rodriguez, K.; Bartel, M.; RamirezAnguita, J. M.; Dutt, S.; Wilch, C.; Kla ̈ rner, F.-G.; Sanchez-Garcia, E.; Schrader, T.; Ottmann, C. Molecular Tweezers Modulate 14-3-3 Protein-Protein Interactions. Nat. Chem. 2013 , 5 (3), 234 -239. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Several residues surround the second hydrophobic moiety of the inhibitors, whereas there are only weak interactions between this part of the inhibitor and protein residues.

    “By contrast, several residues surround the second hydrophobic moiety of the inhibitors, whereas there are only weak interactions between this part of the inhibitor and protein residues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] (139) Hu, G.; Cao, Z.; Xu, S.; Wang, W.; Wang, J. Revealing the Binding Modes and the Unbinding of 14-3-3 σ Proteins and Inhibitors by Computational Methods. Sci. Rep. 2015 , 5 , 16481. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    With a C12-dehydroxy fusicoccane like 22, concomitant binding of a 'mode I' or 'mode II' 14-3-3 partner like C-Raf and consequently its stabilization is possible.

    “With a C12-dehydroxy fusicoccane like 22 , concomitant binding of a ' mode I ' or ' mode II ' 14-3-3 partner like C-Raf and consequently its stabilization is possible (Figure 16B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] (150) Anders, C.; Higuchi, Y.; Koschinsky, K.; Bartel, M.; Schumacher, B.; Thiel, P.; Nitta, H.; Preisig-Mu ̈ ller, R.; Schlichtho ̈ rl, G.; Renigunta, V.; Ohkanda, J.; Daut, J.; Kato, N.; Ottmann, C. A Semisynthetic Fusicoccane Stabilizes a Protein-Protein Interaction and Enhances the Expression of K + Channels at the Cell Surface. Chem. Biol. 2013 , 20 (4), 583 -593. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Because aspartic acid and glutamic acid residues have negative charges, they repel the phosphate group and attract residues with positive charge in the binding pocket.

    “Because the aspartic acid and glutamic acid residues have negative charges, they repel the phosphate group and attract the residues with positive charge in the binding pocket.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] (139) Hu, G.; Cao, Z.; Xu, S.; Wang, W.; Wang, J. Revealing the Binding Modes and the Unbinding of 14-3-3 σ Proteins and Inhibitors by Computational Methods. Sci. Rep. 2015 , 5 , 16481. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fusicoccin A (21) is a diterpene glycoside produced by the phytopathogenic fungus Phomopsis amygdali (formerly Fusicoccum amygdali) that was initially described in the mid-1960s as a wilt-inducing toxin.

    “Fusicoccin A ( 21 ) is a diterpene glycoside produced by the phytopathogenic fungus Phomopsis amygdali (formerly Fusicoccum amygdali ) that was initially described in the mid-1960s to be a wilt-inducing toxin. 141”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] (141) Ballio, A.; Chain, E. B.; de Leo, P.; Erlanger, B. F.; Mauri, M.; Tonolo, A. Fusicoccin: A New Wilting Toxin Produced by Fusicoccum Amygdali Del. Nature 1964 , 203 , 297 -297. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Compound 22 is a natural product produced by a fungus (Cladosporium sp. 501-7W) that acts as a bioactive substance against plants.

    “Compound 22 is another natural product produced by a fungus ( Cladosporium sp. 501-7W) that acts as a bioactive substance against plants. 145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] (145) Sassa, T.; Tojyo, T.; Munakata, K. Isolation of a New Plant Growth Substance with Cytokinin-like Activity. Nature 1970 , 227 , 379. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 21 stabilizes the 14-3-3 interaction with the C-terminus of the F-domain of estrogen receptor α and thus inhibits ERα-dependent transcription.

    “Compound 21 also stabilizes the 14-3-3 interaction with the C-terminus of the F-domain of estrogen receptor α (ER α ) and thus inhibits ER α -dependent transcription. 144”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] (144) De Vries-van Leeuwen, I. J.; da Costa Pereira, D.; Flach, K. D.; Piersma, S. R.; Haase, C.; Bier, D.; Yalcin, Z.; Michalides, R.; Feenstra, K. A.; Jime ́ nez, C. R.; de Greef, T. F. A.; Brunsveld, L.; Ottmann, C.; Zwart, W.; de Boer, A. H. Interaction of 14-3-3 Proteins with the Estrogen Receptor Alpha F Domain Provides a Drug Target Interface. Proc. Natl. Acad. Sci. U. S. A. 2013 , 110 (22), 8894 -8899. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Low glucose leads to phosphorylation of Ser196 of ChREBP by PKA followed by complexation with 14-3-3 and cytoplasmic sequestration.

    “Low glucose leads to phosphorylation of Ser196 of ChREBP by PKA followed by complexation with 14-33 and cytoplasmic sequestration. 161”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] (161) Sakiyama, H.; Wynn, R. M.; Lee, W. R.; Fukasawa, M.; Mizuguchi, H.; Gardner, K. H.; Repa, J. J.; Uyeda, K. Regulation of Nuclear Import/export of Carbohydrate Response Element-Binding Protein (ChREBP): Interaction of An α -Helix of ChREBP with the 143-3 Proteins and Regulation by Phosphorylation. J. Biol. Chem. 2008 , 283 (36), 24899 -24908. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Both β-HB and AcAc stabilize 14-3-3 binding to ChREBP.

    “Both β -HB and AcAc have been shown to stabilize 14-3-3 binding to ChREBP, 162”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] (162) Nakagawa, T.; Ge, Q.; Pawlosky, R.; Wynn, R. M.; Veech, R. L.; Uyeda, K. Metabolite Regulation of Nucleo-Cytosolic Trafficking of Carbohydrate Response Element-Binding Protein (ChREBP): Role of Ketone Bodies. J. Biol. Chem. 2013 , 288 (39), 28358 -28367. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Binding of a competing molecule in the 14-3-3 binding groove will cause inhibition of binding of most other 14-3-3 binding partners, potentially leading to many side effects.

    “This is most strikingly illustrated by 14-3-3 PPI inhibitors, where binding of a competing molecule in the 14-3-3 binding groove will cause inhibition of binding of most other 14-3-3 binding partners, potentially leading to many side e ff ects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ChREBP is a glucose-responsive transcription factor that is implicated in the regulation of fat storage in the liver by facilitating the conversion of carbohydrate to fat.

    “ChREBP is a glucose-responsive transcription factor that is implicated in the regulation of fat storage in the liver by facilitating the conversion of carbohydrate to fat. 159,160”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] (159) Ishii, S.; Iizuka, K.; Miller, B. C.; Uyeda, K. Carbohydrate Response Element Binding Protein Directly Promotes Lipogenic Enzyme Gene Transcription. Proc. Natl. Acad. Sci. U. S. A. 2004 , 101 (44), 15597 -15602. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [160] (160) Iizuka, K.; Bruick, R. K.; Liang, G.; Horton, J. D.; Uyeda, K. Deficiency of Carbohydrate Response Element-Binding Protein (ChREBP) Reduces Lipogenesis as Well as Glycolysis. Proc. Natl. Acad. Sci. U. S. A. 2004 , 101 (19), 7281 -7286. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    The phosphate group of 31 binds to Lys51, Arg58, Arg129, and Tyr130 residues, which are also used to accommodate the phosphorylated motifs of 14-3-3 partner proteins.

    “The phosphate group binds to Lys51, Arg58, Arg129, and Tyr130 residues, which are also used to accommodate the phosphorylated motifs of 14-3-3 partner proteins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] (158) Sato, S.; Jung, H.; Nakagawa, T.; Pawlosky, R.; Takeshima, T.; Lee, W. R.; Sakiyama, H.; Laxman, S.; Wynn, R. M.; Tu, B. P.; MacMillan, J. B.; De Brabander, J. K.; Veech, R. L.; Uyeda, K. Metabolite Regulation of Nuclear Localization of Carbohydrate-Response ElementBinding Protein (ChREBP): Role of Amp as an Allosteric Inhibitor. J. Biol. Chem. 2016 , 291 (20), 10515 -10527. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The finding that β-HB and AcAc stabilize 14-3-3 binding to ChREBP was later extended to compound 31, including a structural biology explanation for this activity.

    “a fi nding that was later extended to 31 including a convincing structural biology explanation for this activity. 158”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] (158) Sato, S.; Jung, H.; Nakagawa, T.; Pawlosky, R.; Takeshima, T.; Lee, W. R.; Sakiyama, H.; Laxman, S.; Wynn, R. M.; Tu, B. P.; MacMillan, J. B.; De Brabander, J. K.; Veech, R. L.; Uyeda, K. Metabolite Regulation of Nuclear Localization of Carbohydrate-Response ElementBinding Protein (ChREBP): Role of Amp as an Allosteric Inhibitor. J. Biol. Chem. 2016 , 291 (20), 10515 -10527. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Compound 25 binds 14-3-3 with a Kd value of 0.37 μM, stronger than the interaction with a PMA2-derived phosphopeptide (Kd = 1.24 μM).

    “was shown to bind 14-3-3 with a K d value of 0.37 μ M, stronger even than the interaction with a PMA2-derived phosphopeptide ( K d = 1.24 μ M). 152”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] (152) Parvatkar, P.; Kato, N.; Uesugi, M.; Sato, S. I.; Ohkanda, J. Intracellular Generation of a Diterpene-Peptide Conjugate That Inhibits 14-3-3-Mediated Interactions. J. Am. Chem. Soc. 2015 , 137 (50), 15624 -15627. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Fusicoccane-peptide hybrid 25 induced cell death, presumably through inhibition of 14-3-3 PPIs.

    “Ohkanda, Kato, and co-workers elegantly demonstrated the power of intracellular oxime ligation to generate a fusicoccane -peptide hybrid ( 25 ) that induced cell death, presumably through inhibition of 14-3-3 PPIs (Figure 14). 152”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] (152) Parvatkar, P.; Kato, N.; Uesugi, M.; Sato, S. I.; Ohkanda, J. Intracellular Generation of a Diterpene-Peptide Conjugate That Inhibits 14-3-3-Mediated Interactions. J. Am. Chem. Soc. 2015 , 137 (50), 15624 -15627. -

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Such molecules act as molecular glue and thereby provide better opportunities for selectivity.

    “In this manner, they act as molecular glue and thereby provide better opportunities for selectivity.”
    Quote in the paperSubstantial claim
77 of 77

  • The paper relies on this without support.

    14-3-3 proteins serve purely as adapter proteins.

    “The fact that 14-3-3 proteins serve purely as adapter proteins means that active compounds against 14-3-3 alone will impact several binding partners and thus likely give rise to unwanted pharmacology.”

  • The paper relies on this without support.

    The respective PPI interfaces of 14-3-3 complexes have relatively high variability.

    “This is due to the relatively high variability between the respective PPI interfaces.”

  • The paper relies on this without support.

    In most documented cases a single 14-3-3 dimer binds to two phosphorylated sites that lie in tandem in the same target protein.

    “Although there are a few cases where a 14-3-3 dimer interacts simultaneously with phosphorylated sites in two di ff erent targets, in most documented cases a single 14-3-3 dimer binds to two phosphorylated sites that lie in tandem in the same target protein.”

  • The paper relies on this without support.

    FOXO3A is a Forkhead-family transcription factor inactivated by Akt1 phosphorylation and subsequent 14-3-3 binding.

    “FOXO3A is a member of the Forkhead family of transcription factors that is inactivated by Akt1 phosphorylation and subsequent 14-3-3 binding.”

  • The paper relies on this without support.

    Phosphorylated HSP20 interacts with 14-3-3 proteins, and the complex regulates cofilin.

    “The phosphorylated form of HSP20 (phospho-HSP20) interacts with 14-3-3 proteins, the complex playing a regulating role on the actin depolymerizing protein co fi lin.”

  • The paper relies on this without support.

    Phospho-HSP20 competes with phospho-cofilin for binding to 14-3-3 proteins, freeing phospho-cofilin, resulting in its dephosphorylation and subsequent depolymerization of the actin cytoskeleton.

    “Phospho-HSP20 competition with phosphoco fi lin for binding to 14-3-3 proteins frees phospho-co fi lin, resulting in its dephosphorylation and subsequent depolymerization of the actin cytoskeleton.”

  • The paper relies on this without support.

    Free phospho-HSP20 can directly destabilize the cytoskeleton.

    “Free phosho-HSP20 is additionally able to directly destabilize the cytoskeleton.”

  • The paper relies on this without support.

    HRas is a common human oncogene, and HRAS protein plays a key role in cancer cell migration.

    “HRas is a common human oncogene, and HRAS protein plays a key role in cancer cell migration.”

  • The paper relies on this without support.

    HRAS activity is dependent on posttranslational prenylation (farnesylation) by FT, which leads to activation of HRAS by membrane localization.

    “HRAS activity is dependent on posttranslational prenylation (farnesylation) by FT, which leads to activation of HRAS by membrane localization.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Degradation of SALL4 leads to teratogenic effects while degradation of Ikaros is a proven chemotherapeutic strategy.

    “Paradoxically, degradation of the former leads to teratogenic effects while degradation of the latter is a proven chemotherapeutic strategy4,6.”

    From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [6]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 18C is cited but not described in the figure caption

    Minor

    The text directs readers to Figure 18C, whereas the Figure 18 caption identifies only panels A and B.

  • Mode II motif places arginine at −4, not −3

    Minor

    The stated mode II sequence has four residues between its arginine and phosphorylated serine, placing the arginine at position −4 rather than the stated −3.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 15

  1. Jason-Moller L., 2006, Curr. Protoc. Protein Sci.
  2. Perrin M. F., 1926, J. Phys. (Paris), 7, 390
  3. Bazin H., 2002, J. Biotechnol., 82, 233
  4. Issad, T.; Jockers, R.InMethods in Molecular Biology, Transmembrane Signalling Protocols;Ali, H.; Haribabu, B., Eds.Humana Press:Totowa, NJ, 2006; Vol.332, p195.
  5. Kocan M., 2010, Front. Endocrinol., 1, 12
  6. Wells J. A., 2007, Nature, 450, 1001, 10.1038/nature06526 · DOI
  7. Chang Y. S., 2013, Proc. Natl. Acad. Sci. U.S.A., 110, E3445
  8. Ross N. T., 2010, Philos. Trans. A Math. Phys. Eng. Sci., 368, 989
  9. Böttger V., 1996, Oncogene, 13, 2141
  10. Hudson E. P., 2012, Sci. Rep., 2
  11. He M., 2009, Nat. Biotechnol., 26, 277
  12. Van Molle I., 2012, Chem. Biol., 19, 1300, 10.1016/j.chembiol.2012.08.015 · DOI
  13. Renner S., 2009, Nat. Chem. Biol., 5, 585, 10.1038/nchembio.188 · DOI
  14. Greaney, M. F.; Bhat, V. T.InDynamic Combinatorial Chemistry;Miller, B. L., Ed.John Wiley & Sons, Inc.:New York, 2009; p43.
  15. Svennelid F., 1999, Plant Cell, 11, 2379

Cited by

Sorted by citations

Related

Authors
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C.
Affiliations
  • Eindhoven University of Technology (NL)
  • Max Planck Society (DE)
Corresponding author
Ottmann, Christian
ORCID
Venue
Chemical Reviews
Publisher
American Chemical Society (ACS)
Published
2014-04-15
Volume
114
Issue
9
Pages
4695-4748
ISSN
  • 0009-2665 (ISSN-L)
  • 1520-6890
DOI
10.1021/cr400698c
OpenAlex
W2145501898
Cited by
497
References
624
Citations by year
2026: 18 · 2025: 35 · 2024: 37 · 2023: 31 · 2022: 33 · 2021: 50 · 2020: 48 · 2019: 42 · 2018: 49 · 2017: 50 · 2016: 44 · 2015: 51 · 2014: 9
FWCI
5.05
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Chemical Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • TU/e Research Portal (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
protein-protein interaction, 14-3-3 proteins, small molecules, peptidomimetics, natural products, protein complex stabilization, undruggable targets, drug discovery
MeSH terms
Ligands, Protein Binding, Proteins, Structure-Activity Relationship, Small Molecule Libraries

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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