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Cited by 67Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries

Open access
Wang, Bo, Liu, Jin, Tandon, Ira, Wu, Suzhen, Teng, Peng, Liao, Jianhua, Tang, Weiping·2021·European Journal of Medicinal Chemistry
DOI 10.1016/j.ejmech.2021.113425PMC PMC8165035
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Abstract

Proteolysis targeting chimeras (PROTACs) have gained tremendous interest in both the academic and pharmaceutical communities. This opens a new way to regulate the cellular protein homeostasis, especially for disease-related proteins. In this work, we designed and synthesized a series of MDM2 degraders based on ligands that were readily prepared by a four-component Ugi reaction. After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines. Surprisingly, our mechanistic investigations indicated that WB214 not only effectively induced the degradation of MDM2, but also led to the degradation of p53. Further studies revealed that WB214 degraded MDM2 as a molecular glue. WB214 and its related analogues did not bind to MDM2 in the p53 binding region and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Finally, we found that WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth. A selective degrader for GSPT1 over MDM2 was then developed through systematically varying different motifs.

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Crossref · 10.1016/j.ejmech.2021.113425

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Claims the paper makes

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  • Findingown data

    WB214 was the most potent anti-proliferative compound among the optimized MDM2 degraders across multiple leukemia cell lines.

    “After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines.”
    • Also stated in: § Introduction · plain
      “After extensive optimization based on anti-proliferation and MDM2 degradation, we developed WB214 as the most potent MDM2 degrader and anti-proliferative agent in various leukemia cell lines.”
    Quote in the paperSubstantial claim
  • Findingown data

    Most degraders in the 3-11 series inhibit RS4;11 leukemia cell growth with lower IC50s than MDM2 ligand 1.

    “Compared to MDM2 ligand 1, most of the degraders exhibit inhibitory activity in RS4;11 leukemia cells with lower IC50s.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Potency of compounds 13, 14, and 15 decreases as linker length increases.

    “The potency of compounds 13, 14, 15 decrease along with the increasing linker length.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    Switching R1 from H to 4-chloro and then to 3,4,5-trifluoro significantly increases anti-proliferation.

    “When group R1 is switched from H to 4-chloro, and then to 3,4,5-trifluoro, the anti-proliferation effect is significantly increased, which can likely be attributed to the increasing hydrophobic interactions with MDM2 protein.”
    Quote in the paperSubstantial claim
  • Findingown data

    WB214 potently degrades GSPT1.

    “WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth.”
    • Also stated in: § WB214 degrades GSPT1, which rationalizes the inhibition of cell growth · boosted
      “WB214 exhibits the most potent GSPT1 degradation, in accordance with its most potent anti-proliferation activity.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 38
  • Probably not a substantial claim. 55
  • The quote only partly states this claim. 2

  • It may state two separate claims as one.

    Findingcitation

    WB156 effectively depletes MDM2 and activates p53.

    “WB156 showed effective depletion of MDM2 and activation of p53 (Figure 2A) as reported previously.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Compounds 3-15 all downregulate p53 along with degrading MDM2.

    “Other compounds (3–15) of this series were then screened by Western blot analysis and downregulation of p53 was observed in all cases, along with the degradation of MDM2 (Figure S2).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Compound 19 causes the most degradation of MDM2 and p53 among compounds 18-21 at 1 μM, though less effective than WB214.

    “Western blotting analysis indicates that 19 exhibits the most degradation of MDM2 and p53 at 1 μM, although it is less effective than WB214 (Figure 2E).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    WB214 downregulates MDM2 and p53 in a dose-dependent manner, with DC50 values of 4.1 nM and 29 nM respectively.

    “Furthermore, protein levels of both MDM2 and p53 were downregulated in the dose-dependent manner (Figure 2C), with a DC50 of 4.1 nM and 29 nM, respectively (Figure 2D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Ligand 1 competes fluorescent peptide PMDM6-F off MDM2 with Ki 0.8 μM, correlating with reported literature value (Ki=0.4 μM).

    “Ligand 1 competes fluorescent peptide (PMDM6-F) off of MDM2 with a Ki value of 0.8 μM, which correlates with the reported literature value (Ki= 0.4 μM)[28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Huang, 2012, Exhaustive fluorine scanning towards potent p53-mdm2 antagonists, ChemMedChem source

  • It may state two separate claims as one.

    Findingcitation

    WB138 increases levels of both p53 and MDM2, consistent with previous reports on MDM2 inhibitors.

    “WB138 increases the levels of both p53 and MDM2, which is consistent with the activity of previous reports on MDM2 inhibitors[28,32–36].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [28] Huang, 2012, Exhaustive fluorine scanning towards potent p53-mdm2 antagonists, ChemMedChem source
    • cites [32] Vassilev, 2004, In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, Science source
    • cites [33] Ding, 2006, Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2−p53 interaction, J. Med. Chem. source
    • cites [34] Ding, 2013, Discovery of RG7388, a potent and selective p53–MDM2 inhibitor in clinical development, J. Med. Chem. source
    • cites [35] Vu, 2013, Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development, ACS Med. Chem. Lett. source
    • cites [36] Sun, 2014, Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2–p53 inhibitor in clinical development, J. Med. Chem. source

  • It may state two separate claims as one.

    Findingown data

    In the 18-21 series, compounds 18 and 19 with shorter linkers inhibit cell proliferation more potently, though much weaker than WB214.

    “For this series of compounds, compounds 18 and 19 with shorter linker lengths exhibit more potent inhibition of cell proliferation, though they are much weaker than WB214.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Co-treatment with WB138 (10 μM) yields the same outcome as ligand 1: p53 degradation rescued, MDM2 degradation persists.

    “The addition of 10 μM WB138, the MDM2 ligand of WB156, yielded the same outcome.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    WB214 does not compete off fluorescent peptide, indicating it does not bind the p53 binding pocket of MDM2.

    “For compound WB214, it does not compete off the fluorescent peptide at all, indicating that it does not bind to the p53 binding pocket of MDM2.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Co-treatment with ligand 1 (10 μM) rescues p53 degradation but not MDM2 degradation by WB214.

    “By co-treatment of cells with ligand 1 (10 μM) and WB214 (100 nM), p53 degradation was rescued. However, the degradation of MDM2 persisted.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Compounds 24a and 27a were obtained in 26% and 24% yields, respectively.

    “compounds 24a (26%) and 27a (24%) were obtained.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Compound 24, with the shortest linker, is the most potent in its series and displays significant MDM2 and GSPT1 degradation.

    “Compound 24 with the shortest linker is the most potent one in this series and displays significant MDM2 degradation, as well as GSPT1 degradation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 8 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Compounds 22 and 23 were obtained in 28% and 42% yields, respectively.

    “giving compounds 22 (28%) and 23 (42%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compounds 18a-21a were obtained in yields of 55% to 74%.

    “giving the desired compound 18a-21a with the yields of 55%−74%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    CC-885 treatment downregulates MDM2 and p53.

    “When cells were treated with CC-885, we observed the downregulation of MDM2 and p53.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    WB214 exhibits the most potent GSPT1 degradation, in accordance with its most potent anti-proliferation activity.

    “WB214 exhibits the most potent GSPT1 degradation, in accordance with its most potent anti-proliferation activity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Neither MDM2 nor GSPT1 is depleted by compound 35 in RS4;11 cells.

    “Western blot analysis showed that neither MDM2 nor GSPT1 could be depleted by compound 35 in RS4;11 cells.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Compound 32 degrades both MDM2 and GSPT1, though with slightly decreased potency.

    “It degraded both MDM2 and GSPT1 (Figure 7C), though with slightly decreased potency.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Meta-substituted compound 22 displays cell growth inhibition and degradation of MDM2, p53, and GSPT1.

    “we observed that meta-substituted compound 22 displayed cell growth inhibition and the degradation of MDM2 and p53 along with GSPT1 degradation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 9 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 10 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    By varying motifs in WB214, compound 36 was discovered that selectively degrades GSPT1 over MDM2, though with weaker potency.

    “Taken together, by varying different motifs in compound WB214, we discovered compound 36 that could selectively degrade GSPT1 over MDM2, though with weaker potency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Compounds 22a and 23a were obtained in 21% and 31% yields, respectively.

    “giving compounds 22a (21%) and 23a (31%).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Both WB156 and WB214 induce ternary complex formation efficiently in a dose-dependent manner, and WB214 induces CRBN-MDM2 interaction more potently.

    “Both WB156 and WB214 could induce the formation of ternary complexes efficiently in a dose-dependent manner and WB214 induced CRBN-MDM2 interaction more potently (Figure 3D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ternary complex formation is a prerequisite for ubiquitin transfer and subsequent proteasomal degradation.

  • It may state two separate claims as one.

    Findingown data

    Compound 36 selectively degrades GSPT1 over MDM2, though with compromised potency.

    “Gratifyingly, compound 36 induced the selective degradation of GSPT1 over MDM2, though with the compromise of potency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compounds 18-21 were obtained in yields of 30% to 71%.

    “giving compounds 18-21 as light-yellow foam with the yields of 30%−71%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Compounds 30 and 31 exhibit the highest potency among rigid-linker compounds, even compared to WB214, but show no selective degradation between MDM2 and GSPT1.

    “Although these two compounds exhibited the highest potency among the compounds with rigid linkers, even in comparison to WB214, there was no selective degradation between MDM2 and GSPT1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 17 was obtained in 49% yield.

    “giving compound 17 (27 mg, 49%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 16 was obtained in 14% yield.

    “giving compound 16 as the light-yellow foam with the yield of 14%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compounds 24-29 were obtained in yields of 26% to 70%.

    “giving the desired compound 24–29 with the yields of 26%−70%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    WB214 depletes GSPT1 in a dose-dependent manner with DC50 0.64 nM.

    “It depletes GSPT1 in a dose-dependent manner (DC50= 0.64 nM) as shown in Figure 4B and 4C.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    None of para-substituted compounds 27-29 inhibit cell growth or induce degradation.

    “Interestingly, none of the para-substituted compounds 27–29 showed any inhibition of cell growth (Figure 6B, dot line), nor did they induce degradation (Figure 6C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 11c was obtained in 76% yield.

    “giving the desired compound 11c (44 mg, 76%).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Compared to WB156, ternary complex forms more efficiently in WB214-treated cells, consistent with its high MDM2 degradation efficacy.

    “Compared to WB156, ternary complex is formed more efficiently in WB214 treated cells, which is consistent with its high efficacy of MDM2 degradation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ternary complex formation is a prerequisite for ubiquitin transfer and subsequent proteasomal degradation.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 37 was obtained in 44% yield.

    “giving compounds 37 (44%) and 38 (71%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 20 has an LC-MS purity of 97%.

    “LC-MS purity: 97%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The Ugi reaction intermediate 31a was produced with a 29% yield.

    “giving compounds 30a (43%) and 31a (29%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 11 (WB214) has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 31 showed an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 18 has an LC-MS purity of 98%.

    “LC-MS purity: 98%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 12 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 24 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 19 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 27 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 17 has an LC-MS purity greater than 99%.

    “LC-MS purity: >99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingown data

    Compound 34 showed an LC-MS purity of 99%.

    “LC-MS purity: 99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The final compound 30 was obtained in 65% yield after Sonogashira coupling.

    “giving compounds 30 (65%) and 31 (45%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 33 showed an LC-MS purity of 99%.

    “LC-MS purity: 99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingown data

    Compound 37 showed an LC-MS purity of 99%.

    “LC-MS purity: 99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 15 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.

    Findingown data

    Compound 32 showed an LC-MS purity of 97%.

    “LC-MS purity: 97%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 26 has an LC-MS purity greater than 99%.

    “LC-MS purity: >99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 30 showed an LC-MS purity of 97%.

    “LC-MS purity: 97%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 16 has an LC-MS purity greater than 99%.

    “LC-MS purity: >99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 38a was obtained in 86% yield.

    “giving the desired compounds 37a (80%) and 38a (86%)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The Ugi reaction intermediate 30a was produced with a 43% yield.

    “giving compounds 30a (43%) and 31a (29%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 37a was obtained in 80% yield.

    “giving the desired compounds 37a (80%) and 38a (86%)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 23 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The final compound 31 was obtained in 45% yield after Sonogashira coupling.

    “giving compounds 30 (65%) and 31 (45%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 36 showed an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 28 has an LC-MS purity greater than 99%.

    “LC-MS purity: >99%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The final compounds 32 through 36 were obtained in yields between 41% and 95%.

    “giving compounds 32–36 as light-yellow foam with the yields of 41%−95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 21 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 13 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 35 showed an LC-MS purity of 98%.

    “LC-MS purity: 98%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 14 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.

    Findingown data

    Compound 38 showed an LC-MS purity of 97%.

    “LC-MS purity: 97%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The Ugi reaction intermediates 32a through 36a were obtained in yields between 27% and 59%.

    “giving compounds 32a-36a with the yields of 27%−59%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 38 was obtained in 71% yield.

    “giving compounds 37 (44%) and 38 (71%) as light-yellow foam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 22 has an LC-MS purity of 95%.

    “LC-MS purity: 95%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Compound 25 has an LC-MS purity of 96%.

    “LC-MS purity: 96%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    WB156 depletes MDM2 efficiently and activates wild-type p53 in leukemia cells, inducing apoptosis.

    “Degrader WB156 depletes MDM2 efficiently and activates wild type p53 in leukemia cells, which further induces the cellular apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Wang, 2019, Development of selective small molecule MDM2 degraders based on nutlin, Eur. J. Med. Chem. source

  • It may state two separate claims as one.

    Interpretationcitation

    The loss of potency of compound 16 is likely due to poor cellular permeability, consistent with the cellular inactivity of parent ligand 2.

    “This is likely due to the poor cellular permeability, which is also correlated to the cellular inactivity of its parent ligand 2 [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Skalniak, 2019, A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53wt osteosarcoma cells, FEBS J. source

  • It may state two separate claims as one.

    Interpretationcitation

    p53 degradation by WB214 is due to its direct association with MDM2, because blocking MDM2-p53 interaction abolishes p53 but not MDM2 degradation.

    “These co-treatment results revealed that p53 degradation is due to its direct association with MDM2 because compounds are known to block the interaction between MDM2 and p53 could abolish the degradation of p53 but not MDM2 by WB214[37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Kussie, 1996, Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain, Science source

  • It may state two separate claims as one.

    Premisecitation

    In the co-crystal structure of an Ugi ligand with MDM2, 4-chlorophenyl, tert-butyl amide, and 6-chloroindole are buried in the binding pocket, while formamide and indole ethyl ester face solvent.

    “The co-crystal structure of Ugi ligand and MDM2 (Figure 1B), shows that 4-chlorophenyl, tert-butyl amide and 6-chloroindole are all deeply buried in the binding pocket[28]. Both the formamide and ethyl ester of indole are pointing towards solvent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Huang, 2012, Exhaustive fluorine scanning towards potent p53-mdm2 antagonists, ChemMedChem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The purities of all title compounds are at least 95%.

    “The purities of all title compounds are ≥95%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    MG-227, a GSPT1 molecular glue derived from an MDM2 PROTAC, has moderate MDM2 degradation but potent p53-independent anti-proliferation, with GSPT1 identified as its target.

    “Recently, the Wang’ group also serendipitously discovered a molecular glue (MG-227) of GSPT1 by simple structural modification of a bona fide MDM2 PROTAC molecule[39]. MG-227 displays only moderate MDM2 degradation effect but with highly potent cell growth inhibition in a p53-independent manner. By unbiased proteomic study, GSPT1 was identified as the target of MG-227.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Matyskiela, 2018, A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos, J. Med. Chem. source

  • It may state two separate claims as one.

    Interpretationown data

    Co-treatment of CC-885 with MG132, MLN4924, or lenalidomide abolishes degradation of GSPT1, MDM2, and p53, indicating MDM2 degradation depends on CRBN E3 ligase and ubiquitin-proteasome system.

    “Moreover, co-treatment of CC-885 with MG132 (5μM), MLN4924 (3μM), or lenalidomide (20μM), abolished the effect of CC-885 for the degradation of GSPT1, MDM2, and p53, indicating that MDM2 degradation depends on the recruitment of CRBN E3 ligase and ubiquitin proteasome system (Figure 5B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Incorporating an E3 ligase ligand into heterobifunctional molecules can often retain degradation activity for neo-substrates, and anti-proliferation can be caused by off-target effects.

    “One lesson we learned from this work is that the incorporation of an E3 ligase ligand into heterobifunctional molecules can often still retain its degradation activity for neo-substrates and the anti-proliferation can be caused by off-target effect.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    p53 degradation by CC-885 is due to its interaction with MDM2, since AMG232 completely blocks p53 degradation.

    “Likewise, p53 degradation is due to its interaction with MDM2 as in the case of WB214, since the co-treatment of cells with AMG232 (a potent MDM2-p53 inhibitor) can completely block the degradation of p53.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Thalidomide-based c-Met PROTAC degrades GSPT1, as observed by proteomic analysis.

    “Crews and his co-workers demonstrated that the degradation of GSPT1 induced by thalidomide-based c-Met PROTAC molecule was observed by the proteomic analysis[42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bondeson, 2018, Lessons in PROTAC design from selective degradation with a promiscuous warhead, Cell Chem. Biol. source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    GSPT1, a CRBN neo-substrate, can be efficiently degraded by CC-885 or ZXH1-161, contributing significantly to inhibition of leukemia cell proliferation.

    “GSPT1, as a neo-substrate of CRBN, can be efficiently degraded by CC-885[15] or ZXH1–161 (a lenalidomide derivative)[41], contributing significantly to the inhibition of leukemia cell proliferation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Matyskiela, 2016, A novel cereblon modulator recruits GSPT1 to the CRL4 CRBN ubiquitin ligase, Nature source
    • cites [41] Powell, 2020, Selective degradation of GSPT1 by cereblon modulators identified via a focused combinatorial library, ACS Chem. Biol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In the presence of IMiDs, CRBN E3 ligase induces proteasomal degradation of neo-substrates such as IKZF1/3, CK1α, and GSPT1.

    “As described before, in the presence of IMiDs, CRBN E3 ligase induces the proteasomal degradation of a set neo-substrates, such as IKZF1/3[13,39], CK1α[40] and GSPT1[15].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Krönke, 2014, Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells, Science source
    • cites [39] Matyskiela, 2018, A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos, J. Med. Chem. source
    • cites [40] Petzold, 2016, Structural basis of lenalidomide-induced CK1α degradation by the CRL4 CRBN ubiquitin ligase, Nature source
    • cites [15] Matyskiela, 2016, A novel cereblon modulator recruits GSPT1 to the CRL4 CRBN ubiquitin ligase, Nature source

  • It may state two separate claims as one.

    Interpretationown data

    There is no direct interaction between MDM2 and CRBN/DDB1 in the presence of CC-885, and MDM2 degradation by CC-885 is likely indirect.

    “These data indicated that there was no direct interaction between MDM2 and CRBN/DDB1 in the presence of CC-885, and MDM2 degradation induced by CC-885 is likely an indirect effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    GSPT1 is responsible for off-target effects of PROTAC molecules that recruit CRBN.

    “It has also been reported that GSPT1 is responsible for off-target effects for PROTAC molecules that recruit CRBN [42–44].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Bondeson, 2018, Lessons in PROTAC design from selective degradation with a promiscuous warhead, Cell Chem. Biol. source
    • cites [43] Ishoey, 2018, Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders, ACS Chem. Biol. source
    • cites [44] Yang, 2019, Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: a cautionary tale in the design of PROTAC degraders, J. Med. Chem. source

  • It may state two separate claims as one.

    Premisecitation

    GSPT1 is a common neo-substrate of CRBN and contributes greatly to inhibition of cell proliferation.

    “Collectively, GSPT1 is a common neo-substrate of CRBN and it contributes greatly to the inhibition of cell proliferation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    MI-389, initially designed as an RTK degrader, shows significant cell growth inhibition and degrades GSPT1 rather than the intended kinase.

    “MI-389, initially designed as a receptor tyrosine kinases (RTK) degrader shows significant cell growth inhibition. Interestingly, it degrades GSPT1, rather than the intended target kinase[43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Ishoey, 2018, Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders, ACS Chem. Biol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The RS4;11 cells used in the experiments were within 20 passages after purchase.

    “The experiments were performed by using cells within 20 passages after purchasing.”
    Quote in the paperNot a substantial claim
89 of 89

  • The paper relies on this without support.

    The four-component Ugi reaction can generate a diverse range of structures by varying each of the four components.

    “which has the potential to generate a diverse range of structures by varying each of the four components.”

  • The paper relies on this without support.

    Ternary complex formation is a prerequisite for ubiquitin transfer and subsequent proteasomal degradation.

    “Ternary complex formation is the prerequisite for the ubiquitin transfer and the subsequent proteasomal degradation.”
2 of 2

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?

  • WB214 (213) is the most potent antiproliferative agent across various leukemic cell lines; unlike WB156, it does not activate p53 but induces its degradation, and its mechanism more closely resembles a molecular glue.

    “After further optimization, the team identified WB214 (213) as the most potent antiproliferative agent across various leukemic cell lines (Table 4). Unlike WB156, WB214 does not activate p53 but instead induces its degradation, and subsequent investigations revealed that its mechanism of action more closely resembles that of a molecular glue.508”

    From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [508]

  • Targeted MDM2 degradation has the potential to reduce dose-dependent hematological toxicity of MDM2 inhibitors.

    “Targeted MDM2 degradation also had the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors [124–128].”

    From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [126]

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.

  • Compound 18's formula has an extra oxygen

    Minor

    The named structure of compound 18 contains six oxygen atoms, whereas its reported ion formula contains seven.

  • Compounds 6-8 list too few chlorine atoms

    Minor

    Compound 6's name contains both a chlorobenzyl and a chloroindole group, but its reported ion formula lists only one chlorine atom. The same mismatch appears in the formulas for compounds 7 and 8.

2 of 2

Citations

The citation lists haven’t been fetched yet

References 47 · Cited by 67

Metadata

Authors
Wang, B., Liu, J., Tandon, I., Wu, S., Teng, P., Liao, J., & Tang, W.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Tang, Weiping
ORCID
Venue
European Journal of Medicinal Chemistry
Publisher
Elsevier BV
Published
2021-07
Volume
219
Pages
113425
ISSN
0223-5234 (ISSN-L)
DOI
10.1016/j.ejmech.2021.113425
PMC
PMC8165035
OpenAlex
W3140378160
Semantic Scholar
78be5885c8a14636de4b6fc9437246ac62f4bb24
Cited by
67
References
47
Citations by year
2026: 5 · 2025: 17 · 2024: 8 · 2023: 16 · 2022: 17 · 2021: 3
FWCI
3.84
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
PROTACs, Ugi reaction, four-component reaction, p53 degradation, molecular glues, cereblon E3 ligase, leukemia, antiproliferative agents, protein degradation
MeSH terms
Cell Survival, Humans, Indoles, Ligands, Protein Binding, Structure-Activity Relationship, Drug Design, Tumor Suppressor Protein p53, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-mdm2, Proteolysis

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