Cited by 175Cancer-related Molecular PathwaysComputational Drug Discovery MethodsCancer Mechanisms and Therapy

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Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches

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Carabet, Lavinia A., Rennie, Paul S., Cherkasov, Artem·2018·International Journal of Molecular Sciences

DOI 10.3390/ijms20010120PMC PMC6337544

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Abstract

Myc (avian myelocytomatosis viral oncogene homolog) represents one of the most sought after drug targets in cancer. Myc transcription factor is an essential regulator of cell growth, but in most cancers it is overexpressed and associated with treatment-resistance and lethal outcomes. Over 40 years of research and drug development efforts did not yield a clinically useful Myc inhibitor. Drugging the “undruggable” is problematic, as Myc inactivation may negatively impact its physiological functions. Moreover, Myc is a disordered protein that lacks effective binding pockets on its surface. It is well established that the Myc function is dependent on dimerization with its obligate partner, Max (Myc associated factor X), which together form a functional DNA-binding domain to activate genomic targets. Herein, we provide an overview of the knowledge accumulated to date on Myc regulation and function, its critical role in cancer, and summarize various strategies that are employed to tackle Myc-driven malignant transformation. We focus on important structure-function relationships of Myc with its interactome, elaborating structural determinants of Myc-Max dimer formation and DNA recognition exploited for therapeutic inhibition. Chronological development of small-molecule Myc-Max prototype inhibitors and corresponding binding sites are comprehensively reviewed and particular emphasis is placed on modern computational drug design methods. On the outlook, technological advancements may soon provide the so long-awaited Myc-Max clinical candidate.

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Dang, C. V., & Lee, W. M. F. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.10.4048-4054.1988 · Cited by 339
Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts
Berg, T., Cohen, S. B., Desharnais, J., Sonderegger, C. K., Maslyar, D. J., Goldberg, J., Boger, D. L., & Vogt, P. K. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062036999 · Cited by 326 · cited 3×
“(2002) [97] from a combinatorial library of approximately 7000 peptidomimetic compounds that have been screened in vitro using the fluorescence resonance energy transfer (FRET) technique.”
BackgroundInfluential
Design and Synthesis of an Expanded Porphyrin That Has Selectivity for the c-MYC G-Quadruplex Structure
Seenisamy, J., Bashyam, S., Gokhale, V., Vankayalapati, H., Sun, D., Siddiqui-Jain, A., Streiner, N., Shin-ya, K., White, E., Wilson, W. D., et al. (2005) · Journal of the American Chemical Society · doi:10.1021/ja0444482 · Cited by 319
Poly(A) Shortening and Degradation of the 3′ A+U-Rich Sequences of Human c- myc mRNA in a Cell-Free System
Brewer, G., & Ross, J. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.4.1697 · Cited by 316 · cited 1×
“The first is translation-independent, involving poly(A) tail shortening that is regulated by AU-rich sequences in the 3′ untranslated region [34,35].”
Background
Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC
Thomas, L. R., Wang, Q., Grieb, B. C., Phan, J., Foshage, A. M., Sun, Q., Olejniczak, E. T., Clark, T., Dey, S., Lorey, S., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.028 · Cited by 310 · cited 1×
“These boxes have been reported to interact with additional effectors, including CREB-binding p300/CBP transcriptional co-activators, and WDR5 (WD repeat-containing protein 5), which stabilizes Myc interactions with chromatin to promote target gene recognition and Myc-driven tumorigenesis [49].”
Background
Inhibition of Myc family proteins eradicates KRas-driven lung cancer in micePreprint
Soucek, L., Whitfield, J. R., Sodir, N. M., Massó-Vallés, D., Serrano, E., Karnezis, A. N., Swigart, L. B., & Evan, G. I. (2013) · Genes & Development · doi:10.1101/gad.205542.112 · Cited by 310 · cited 1×
“Omomyc established the feasibility of intermittent systemic inhibition of Myc-Max protein–protein and protein-DNA interactions for it showed efficacy against tumors with no toxicity to normal tissues, conferring indefinite survival in animal models [23,83].”
Background
Rapid Cytoplasmic Turnover of c-myc mRNA: Requirement of the 3′ Untranslated Sequences
Jones, T. R., & Cole, M. D. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.12.4513-4521.1987 · Cited by 309
MYC and Prostate Cancer
Koh, C. M., Bieberich, C. J., Dang, C. V., Nelson, W. G., Yegnasubramanian, S., & Marzo, A. M. D. (2010) · Genes & Cancer · doi:10.1177/1947601910379132 · Cited by 305
Targeting MYC Expression through G-Quadruplexes
Brooks, T. A., & Hurley, L. H. (2010) · Genes & Cancer · doi:10.1177/1947601910377493 · Cited by 305
Strategies to Inhibit Myc and Their Clinical Applicability
Whitfield, J. R., Beaulieu, M.-È., & Soucek, L. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00010 · Cited by 303
Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma
Brockmann, M., Poon, E., Berry, T., Carstensen, A., Deubzer, H. E., Rycak, L., Jamin, Y., Thway, K., Robinson, S. P., Roels, F., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.05.005 · Cited by 300
The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics
Brooks, T. A., & Hurley, L. H. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2733 · Cited by 299
Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant.Preprint
Bernstein, P., Herrick, D., Prokipcak, R. D., & Ross, J. (1992) · Genes & Development · doi:10.1101/gad.6.4.642 · Cited by 297 · cited 2×
“The second is a translation-dependent mechanism regulated by a region of mRNA corresponding to the C-terminal domain of the coding region determinant-binding protein (CRD-BP) [36].”
Background
Surflex-Dock: Docking benchmarks and real-world application
Spitzer, R., & Jain, A. N. (2012) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-011-9533-y · Cited by 296 · cited 1×
“The Surflex molecular docking [133] module in the Sybyl-X2.”
Method
The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis
Carroll, P. A., Freie, B. W., Mathsyaraja, H., & Eisenman, R. N. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0650-z · Cited by 289 · cited 8×
“The observed changes in the abundance of individual network players have functional consequences that are attributed to the competition for available Max and Mlx core members as well as for DNA-binding sites, and may account in part for the extraordinary tight regulation of Myc expression [13,55,58,59].”
BackgroundInfluential
Drugging MYCN through an Allosteric Transition in Aurora Kinase A
Gustafson, W. C., Meyerowitz, J., Nekritz, E. A., Chen, J., Benes, C. H., Charron, E., Simonds, E. F., Seeger, R. C., Matthay, K. K., Hertz, N. T., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.07.015 · Cited by 284
c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover
Bahram, F., von der Lehr, N., Cetinkaya, C., & Larsson, L. (2000) · Blood · doi:10.1182/blood.v95.6.2104 · Cited by 283
c-MYC promoter G-quadruplex formed at the 5′-end of NHE III 1 element: insights into biological relevance and parallel-stranded G-quadruplex stability
Mathad, R. I., Hatzakis, E., Dai, J., & Yang, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr612 · Cited by 249
Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics
Chen, B.-J., Wu, Y., Tanaka, Y., & Zhang, W. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.10190 · Cited by 247
Clinical trials for BET inhibitors run ahead of the science
Andrieu, G., Belkina, A. C., & Denis, G. V. (2016) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2016.06.004 · Cited by 247 · cited 1×
“, MAPK, mTORC1 and FOXO3a) [30], and inhibitors of Myc chromatin remodeling and transcription of BET bromodomain proteins [85].”
Background
The Expanding World of N-MYC–Driven Tumors
Rickman, D. S., Schulte, J. H., & Eilers, M. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0273 · Cited by 246
Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation
Itzen, F., Greifenberg, A. K., Bösken, C. A., & Geyer, M. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku449 · Cited by 245 · cited 1×
“Acetylated, open chromatin is bound by bromodomain-containing proteins, such as BRD4, and other coactivators of the bromodomain and extra terminal (BET) family, which recruit the positive transcription elongation factor b (P-TEFb) complex at target genes promoters, activate the kinase activity of P-TEFb, which phospho…”
Background
Function and regulation of the transcription factors of the Myc/Max/Mad network
Lüscher, B. (2001) · Gene · doi:10.1016/s0378-1119(01)00697-7 · Cited by 242 · cited 7×
“The observed changes in the abundance of individual network players have functional consequences that are attributed to the competition for available Max and Mlx core members as well as for DNA-binding sites, and may account in part for the extraordinary tight regulation of Myc expression [13,55,58,59].”
BackgroundInfluential
MYC and the Control of ApoptosisPreprint
McMahon, S. B. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014407 · Cited by 240 · cited 1×
“The Mnt factor antagonizes both Myc-stimulated proliferation and apoptosis, its pro-survival function being critical for Myc-driven tumorigenesis consistent with Mnt’s dominant physiological activity of opposing the pro-apoptotic activity elicited by Myc [10].”
Background
Multiple Independent Binding Sites for Small-Molecule Inhibitors on the Oncoprotein c-Myc
Hammoudeh, D. I., Follis, A. V., Prochownik, E. V., & Metallo, S. J. (2009) · Journal of the American Chemical Society · doi:10.1021/ja900616b · Cited by 239 · cited 6×
“Compound 10074-A4, unlike 10058-F4 and 10074-G5, is a non-fluorescent chemical that exists as a racemic mixture of two (R- and S-) enantiomers [99,155].”
BackgroundInfluential
Myc confers androgen-independent prostate cancer cell growth
Bernard, D., Pourtier, A., Gil, J., & Beach, D. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319035 · Cited by 235
Myc-Nick: A Cytoplasmic Cleavage Product of Myc that Promotes α-Tubulin Acetylation and Cell Differentiation
Conacci‐Sorrell, M., Ngouenet, C., & Eisenman, R. N. (2010) · Cell · doi:10.1016/j.cell.2010.06.037 · Cited by 234
Therapeutic Strategies to Inhibit MYCPreprint
McKeown, M. R., & Bradner, J. E. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014266 · Cited by 231 · cited 1×
“A number of structurally-diverse small molecule prototypes have been reported but they lack in vivo efficacy and/or demonstrate suboptimal safety profiles [27,29].”
Background
Design and properties of a Myc derivative that efficiently homodimerizes
Soucek, L., Helmer‐Citterich, M., Sacco, A., Jucker, R., Cesareni, G., & Nasi, S. (1998) · Oncogene · doi:10.1038/sj.onc.1202199 · Cited by 224 · cited 2×
“Omomyc is a dominant negative 93 residue bHLHLZ Myc protein fragment specifically designed to introduce four single-point mutations in the dimerization domain that correspond to four charged amino acids shown to prevent Myc homodimerization due to major steric and electrostatic clashes [81].”
Background
Identification of the human c-myc protein nuclear translocation signal.
Dang, C. V., & Lee, W. M. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.10.4048 · Cited by 221
The c‐myc Promoter: Still MysterY and Challenge
(2008) · Advances in Cancer Research · doi:10.1016/s0065-230x(07)99004-1 · Cited by 211 · cited 9×
“While being essential for normal Myc regulation in minimizing undesired Myc expression, the integrated biological output from the multiple-input signaling networks poses the risks of driving pathological conditions [33].”
BackgroundInfluential
Use of Amino Acid Composition to Predict Ligand-Binding Sites
Soga, S., Shirai, H., Kobori, M., & Hirayama, N. (2007) · Journal of Chemical Information and Modeling · doi:10.1021/ci6002202 · Cited by 204
Binding Site Detection and Druggability Prediction of Protein Targets for Structure- Based Drug Design
Yuan, Y., Pei, J., & Lai, L. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319120019 · Cited by 199
Rapid cytoplasmic turnover of c-myc mRNA: requirement of the 3' untranslated sequences.
Jones, T. R., & Cole, M. D. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.12.4513 · Cited by 191
Improved low molecular weight Myc-Max inhibitors
Wang, H., Hammoudeh, D. I., Follis, A. V., Reese, B. E., Lazo, J. S., Metallo, S. J., & Prochownik, E. V. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0005 · Cited by 191 · cited 2×
“This inconsistent behavior possibly reflected multiple binding modes of singly or dual substituted analogs to different conformations of the intrinsically disordered Myc monomer [104].”
Background
Single amino acid substitutions alter helix‐loop‐helix protein specificity for bases flanking the core CANNTG motif.
Fisher, F. A., & Goding, C. R. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05503.x · Cited by 191 · cited 3×
“The conserved Arg H-bonds the central guanine and in addition interacts with the phosphate group between the cytosine and the adenine at the first and second positions in the hexanucleotide dictating the identity of the central 5′-CG-3′ dinucleotide and the specificity for bHLHLZ proteins that bind the canonical class…”
BackgroundInfluential
PREDITOR: a web server for predicting protein torsion angle restraints
Berjanskii, M. V., Neal, S., & Wishart, D. S. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl341 · Cited by 191 · cited 1×
“Free and bound structures of the above-mentioned Myc peptides were modeled using the PREDITOR web server [152] based on dihedral constraints that were obtained from observed NMR chemical shifts, and further energy minimized using CHARMM27 parameters [153].”
Method
The Max Network Gone Mad
Baudino, T. A., & Cleveland, J. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.3.691-702.2001 · Cited by 183 · cited 2×
“In addition, Max binds to Mga, the largest protein in the Max network and a “dual-specificity” transcription factor, in that possesses not only the bHLHLZ Max DNA binding motif, but also a T-domain DNA binding motif [56].”
Background
Structural Rationale for the Coupled Binding and Unfolding of the c-Myc Oncoprotein by Small Molecules
Follis, A. V., Hammoudeh, D. I., Wang, H., Prochownik, E. V., & Metallo, S. J. (2008) · Chemistry & Biology · doi:10.1016/j.chembiol.2008.09.011 · Cited by 183
Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells
Franke, N. E., Niewerth, D., Assaraf, Y. G., van Meerloo, J., Vojtekova, K., van Zantwijk, C. H., Zweegman, S., Chan, E. T., Kirk, C. J., Geerke, D. P., et al. (2011) · Leukemia · doi:10.1038/leu.2011.256 · Cited by 180
Addiction to c-MYC in multiple myeloma
Holien, T., Våtsveen, T. K., Hella, H., Waage, A., & Sundan, A. (2012) · Blood · doi:10.1182/blood-2011-08-371567 · Cited by 177 · cited 1×
“[130] reported yet another novel inhibitor, 7594-0035, specifically targeting Myc for the potential treatment of relapsed/refractory multiple myeloma (MM), in which frontline therapy-resistance has been associated with Myc [131,132].”
Background
Structure of the Biologically Relevant G-Quadruplex in The c-MYC Promoter
Yang, D., & Hurley, L. H. (2006) · Nucleosides Nucleotides & Nucleic Acids · doi:10.1080/15257770600809913 · Cited by 176
Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression
Thakur, R. K., Kumar, P., Halder, K., Verma, A., Kar, A., Parent, J., Basundra, R., Kumar, A., & Chowdhury, S. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn919 · Cited by 174
Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex
Calabrese, D. R., Chen, X., Leon, E. C., Gaikwad, S. M., Phyo, Z., Hewitt, W. M., Alden, S., Hilimire, T. A., He, F., Michalowski, A. M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06315-w · Cited by 172 · cited 1×
“In a follow-up study, Calabrese et al. (2018) [189], aiming at understanding the molecular determinants of binding affinity and selectivity for G4 structures, synthesized a focused library of 25 analogs of compound 1, as reported earlier by the group [188].”
Background
Cancer therapeutics: Targeting the dark side of Myc
Ponzielli, R., Katz, S., Baršytė-Lovejoy, D., & Penn, L. Z. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.08.017 · Cited by 170
Visualization of Myc/Max/Mad Family Dimers and the Competition for Dimerization in Living Cells
Grinberg, A. V., Hu, C., & Kerppola, T. K. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.10.4294-4308.2004 · Cited by 169 · cited 1×
“In terms of dimerization with Max, Myc, and Mxd network members bind Max with different efficiencies and distinct subcellular localization patterns between Myc-Max and Mxd-Max have been reported [72].”
Background
The c-MYCNHE III1: Function and Regulation
González, V., & Hurley, L. H. (2009) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094649 · Cited by 169
Clinical and molecular features of treatment‐related neuroendocrine prostate cancer
Akamatsu, S., Inoue, T., Ogawa, O., & Gleave, M. E. (2018) · International Journal of Urology · doi:10.1111/iju.13526 · Cited by 162
Stabilization of G‐Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down‐Regulation of c‐ myc Oncogene Expression
Wu, P., Ma, D., Leung, C., Yan, S., Zhu, N., Abagyan, R. A., & Che, C. (2009) · Chemistry - A European Journal · doi:10.1002/chem.200901943 · Cited by 161
Small-molecule inhibitors of the Myc oncoprotein
Fletcher, S., & Prochownik, E. V. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.03.005 · Cited by 160 · cited 3×
“3jc48-3 is considered to be one of the most potent, cellular active, and stable Myc inhibitors fr m the classical series developed by the group [100,103,105,106].”
Background
Discrimination between related DNA sites by a single amino acid residue of Myc-related basic-helix-loop-helix proteins.
Dang, C. V., Dolde, C. E., Gillison, M. L., & Kato, G. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.2.599 · Cited by 159 · cited 1×
“, AP4, homologous bHLHLZ transcription factor) into a canonical class B E-box binding protein [79].”
Background
Selective Inhibition of c-Myc/Max Dimerization and DNA Binding by Small Molecules
Kiessling, A., Sperl, B., Hollis, A., Eick, D., & Berg, T. (2006) · Chemistry & Biology · doi:10.1016/j.chembiol.2006.05.011 · Cited by 152 · cited 2×
“Mycro3 (Figure 7) was identified by Kiessling et al. (2007) [109] via high-throughput screening of a library of 1438 pyrazolo [1,5-α] pyrimidines that were built upon the two predecessor compounds, Mycro1 and Mycro2 [110].”
Background
Inhibitor of MYC identified in a Kröhnke pyridine library
Hart, J. R., Garner, A. L., Yu, J., Ito, Y., Sun, M., Ueno, L. A., Rhee, J., Baksh, M. M., Stefan, E., Hartl, M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1319488111 · Cited by 150 · cited 6×
“(2014) [112] within a 220-membered Kröhnke pyridine combinatorial library [113] screened by a fluorescence polarization assay for the inhibition of Myc-Max dimerization (Figure 7).”
BackgroundInfluential
Design of Modular G‐quadruplex Ligands
Duarte, A. R. P., Cadoni, E., Ressurreição, A. S., Moreira, R., & Paulo, A. (2018) · ChemMedChem · doi:10.1002/cmdc.201700747 · Cited by 138
The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy
Savino, M., Annibali, D., Carucci, N., Favuzzi, E., Cole, M. D., Evan, G. I., Soucek, L., & Nasi, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022284 · Cited by 136 · cited 3×
“Omomyc specifically prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz1-dependent binding to promoters and transregression, mechanisms of action accompanied by broad epigenetic changes [82].”
BackgroundInfluential
Myc and its interactors take shape
Tu, W. B., Helander, S., Pilstål, R., Hickman, K. A., Lourenco, C., Jurišica, I., Raught, B., Wallner, B., Sunnerhagen, M., & Penn, L. Z. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.06.002 · Cited by 130 · cited 2×
“These domains contain highly conserved modules that provide docking sites for a large number of cofactors that regulate Myc activity and stability [16,17].”
Background
A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation
Castell, A., Yan, Q., Fawkner, K., Hydbring, P., Zhang, F., Verschut, V., Franco, M., Zakaria, S. M., Bazzar, W., Goodwin, J., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-28107-4 · Cited by 130 · cited 2×
“[118] study is the demonstration of the effects of MYCMI-6 administration by daily intraperitoneal injection at a dose of 20 mg/kg in vivo, where MYCMI-6 induced massive apoptosis and reduced tumor cell proliferation, tumor microvasculature density, and N-Myc-Max interaction in an N-Myc-dependent mouse xenograft tumor…”
BackgroundMethod
Small Molecule Microarrays Enable the Identification of a Selective, Quadruplex-Binding Inhibitor of MYC Expression
Felsenstein, K. M., Saunders, L. B., Simmons, J. K., Leon, E. C., Calabrese, D. R., Zhang, S., Michalowski, A. M., Gareiss, P. C., Mock, B. A., & Schneekloth, J. S. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00577 · Cited by 129
Binding of Myc Proteins to Canonical and Noncanonical DNA Sequences
Blackwell, T. K., Huang, J., Ma, A., et al. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.9.5216-5224.1993 · Cited by 127 · cited 1×
“Non-canonical sequences, such as 5′-CACGCG-3′ and 5′-CATGGC-3′, represent low-affinity Myc-Max binding sites [21].”
Background
Alternative Forms of Max as Enhancers or Suppressors of Myc-Ras Cotransformation
Mäkelä, T. P., Koskinen, P. J., Västrik, I., & Alitalo, K. K. (1992) · Science · doi:10.1126/science.256.5055.373 · Cited by 124 · cited 2×
“, 160 amino acids in length), ∆Max lacks the C-terminal 61 amino acids, which are replaced by five residues before ending with an alternative exon (Figure 3) [19,70].”
Background
NF-κB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer
Nadiminty, N., Tummala, R., Liu, C., Lou, W., Evans, C. P., & Gao, A. C. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-1057 · Cited by 124
Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice
Guo, J., Parise, R. A., Joseph, E., Egorin, M. J., Lazo, J. S., Prochownik, E. V., & Eiseman, J. L. (2008) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-008-0774-y · Cited by 123 · cited 2×
“Upon single intravenous dose treatment of mice with 20 or 30 mg/kg of 10058-F4, peak tumor concentrations of 10058-F4 were at least 10-fold lower than peak plasma concentrations, eight metabolites were identified in plasma, liver, and kidney, and no significant inhibition of tumor growth has been observed [101].”
Background
Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression
Kim, J. H., Dhanasekaran, S. M., Mehra, R., Tomlins, S. A., Gu, W., Yu, J., Kumar‐Sinha, C., Cao, X., Dash, A., Wang, L., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1297 · Cited by 119
Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc
Chen, Y., Niu, X., Jin, F., Liu, Z., Jin, C., & Lai, L. (2016) · Scientific Reports · doi:10.1038/srep22298 · Cited by 117 · cited 7×
“[25] provided a useful strategy for SBDD targeting intrinsically disordered proteins (IDPs) while also suggesting”
BackgroundMethodInfluential
In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization
Clausen, D. M., Guo, J., Parise, R. A., Beumer, J. H., Egorin, M. J., Lazo, J. S., Prochownik, E. V., & Eiseman, J. L. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.170555 · Cited by 117 · cited 3×
“As in the case of 10058-F4, the peak tumor concentrations were at least 10-fold lower than peak plasma values and as many as 19 inactive metabolites were observed with a number of these appearing to be glucuronide derivatives of hydroxylated or nitro-reduced 10074-G5, products of primary and secondary metabolic biotra…”
Background
c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks
Barfeld, S. J., Urbanucci, A., Itkonen, H. M., Fazli, L., Hicks, J. L., Thiede, B., Rennie, P. S., Yegnasubramanian, S., Marzo, A. M. D., & Mills, I. G. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.006 · Cited by 113
Self-citation
Inhibition of Cell Proliferation by Quindoline Derivative (SYUIQ-05) through its Preferential Interaction with c-myc Promoter G-Quadruplex
Ou, T., Lin, J., Lu, Y., Hou, J., Tan, J., Chen, S., Li, Z., Li, Y., Li, D., Gu, L., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200062u · Cited by 112
The Myc Negative Autoregulation Mechanism Requires Myc-Max Association and Involves the c- myc P2 Minimal Promoter
Facchini, L. M., Chen, S., Marhin, W. W., Lear, J. N., & Penn, L. Z. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.100 · Cited by 110 · cited 1×
“Myc levels are controlled by multiple mechanisms, including negative autoregulation, gene expression, mRNA, and protein stability and degradation, which all become deregulated in human cancers [1,14,15].”
Background
Ligand Clouds around Protein Clouds: A Scenario of Ligand Binding with Intrinsically Disordered Proteins
Jin, F., Chen, Y., Lai, L., & Liu, Z. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003249 · Cited by 108 · cited 4×
“[24] studied the binding characteristics of 10074-A4, the only Myc compound known insofar to bind to the loop region, by using extensive MD simulations, with both implicit and explicit solvent models, and found that 10074-A4 associated with Myc370–409 and behaved like a “ligand cloud” around a “protein cloud”, with di…”
BackgroundMethodInfluential
Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase
Kurland, J. F., & Tansey, W. P. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6552 · Cited by 107 · cited 2×
“repression, as it provides docking sites for components of histone deacetylase repressor complexes, such as SIN3 and HDAC3 [47,48], and MBIV, also important for Myc transcriptional activity and Myc-induced apoptosis.”
Background
Stress-induced cleavage of Myc promotes cancer cell survivalPreprint
Conacci‐Sorrell, M., Ngouenet, C., Anderson, S., Brabletz, T., & Eisenman, R. N. (2014) · Genes & Development · doi:10.1101/gad.231894.113 · Cited by 107
Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects.
Duan, W., Rangan, A., Vankayalapati, H., Kim, M. Y., Zeng, Q., Sun, D., Han, H., Fedoroff, O. Y., Nishioka, D., Rha, S. Y., et al. (2001) · PubMed · Cited by 107
NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III1
Dexheimer, T. S., Carey, S. S., Song, Z., Gokhale, V. M., Hu, X., Murata, L. B., Maes, E. M., Weichsel, A., Sun, D., Meuillet, E. J., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-1093 · Cited by 103
OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors
Jung, L. A., Gebhardt, A., Koelmel, W., Ade, C. P., Walz, S., Kuper, J., von Eyss, B., Letschert, S., Redel, C., d'Artista, L., et al. (2017) · Oncogene · doi:10.1038/onc.2016.354 · Cited by 101 · cited 8×
“Omomyc preferentially forms homodimers that are additionally stabilized by multiple interactions that are not present in the Myc-Max heterodimer, and introduced by specifically designed mutations [80].”
BackgroundInfluential
Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex
Hu, M.-H., Wang, Y.-Q., Yu, Z.-Y., Hu, L.-N., Ou, T.-M., Chen, S.-B., Huang, Z.-S., & Tan, J.-H. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01697 · Cited by 101
Targeting intrinsically disordered proteins in rational drug discovery
Ambadipudi, S., & Zweckstetter, M. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2016.1107041 · Cited by 101
Targeting of the MYCN Protein with Small Molecule c-MYC Inhibitors
Müller, I., Larsson, K., Frenzel, A., Oliynyk, G., Zirath, H., Prochownik, E. V., Westwood, N. J., & Arsenian‐Henriksson, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097285 · Cited by 97
Perturbation of the c-Myc–Max Protein–Protein Interaction via Synthetic α-Helix Mimetics
Jung, K., Wang, H., Teriete, P., Yap, J. L., Chen, L., Lanning, M. E., Hu, A., Lambert, L. J., Holien, T., Sundan, A., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501440q · Cited by 94
MYC Modulation around the CDK2/p27/SKP2 Axis
Hydbring, P., Castell, A., & Larsson, L. (2017) · Genes · doi:10.3390/genes8070174 · Cited by 92
Mnt Loss Triggers Myc Transcription Targets, Proliferation, Apoptosis, and Transformation
Nilsson, J. A., Maclean, K. H., Keller, U. B., Pendeville, H., Baudino, T. A., & Cleveland, J. L. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1560-1569.2004 · Cited by 91 · cited 1×
“It has been demonstrated that the loss of Mnt induces si ilar effects as Myc overexpression, such as enhanced transcription f Myc target genes, resulting in accelerated proliferation, apoptosis, and transfor ation [62,63].”
Background
Therapeutic Effects of an Anti-Myc Drug on Mouse Pancreatic Cancer
Stellas, D., Szabolcs, M. J., Koul, S., Li, Z., Polyzos, A., Anagnostopoulos, C., Cournia, Z., Tamvakopoulos, C., Klinakis, A., & Efstratiadis, A. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju320 · Cited by 87 · cited 6×
“(2014) [111] showed that genetic ablation of MYC effectively prevented the development of KRAS*-induced pancreatic, a ary and prostatic adenocarcino a and penile squa ous cell carcino a in ice (consistent ith o yc data).”
BackgroundResultInfluential
Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD)
Sun, Q.-Y., Ding, L.-W., Tan, K. T., Chien, W., Mayakonda, A., Lin, D.-C., Loh, X.-Y., Xiao, J.-F., Meggendorfer, M., Alpermann, T., et al. (2016) · Leukemia · doi:10.1038/leu.2016.160 · Cited by 87 · cited 1×
“The Mga member of the extended network has been suggested to act as a tumor suppressor, with inactivating mutations detected in leukemia [61].”
Background
Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis
Hurlin, P. J., Zhou, Z., Toyo‐oka, K., Ota, S., Walker, W. L., Hirotsune, S., & Wynshaw-Boris, A. J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg442 · Cited by 86 · cited 2×
“It has been proposed that Myc f nctions by the relief of Mnt repression [63,64].”
Background
Targeting MYC in cancer therapy: RNA processing offers new opportunities
Koh, C. M., Sabò, A., & Guccione, E. (2016) · BioEssays · doi:10.1002/bies.201500134 · Cited by 86 · cited 5×
“Examples include inhibitors of MYC transcription with direct G-quadruplex stabilizers, antisense oligonucleotides that induce MYC mRNA degradation, aberrant splicing of MYC pre-mRNA or translation block, as well as short-interfering RNAs [29,30].”
BackgroundInfluential
Pharmacophore identification of c-Myc inhibitor 10074-G5
Yap, J. L., Wang, H., Hu, A., Chauhan, J., Jung, K.-Y., Gharavi, R. B., Prochownik, E. V., & Fletcher, S. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.10.013 · Cited by 83 · cited 4×
“3jc48-3 is considered to be one of the most potent, cellular active, and stable Myc inhibitors fr m the classical series developed by the group [100,103,105,106].”
BackgroundInfluential
Selective Inhibition of c‐Myc/Max Dimerization by a Pyrazolo[1,5‐a]pyrimidine
Kiessling, A., Wiesinger, R., Sperl, B., & Berg, T. (2007) · ChemMedChem · doi:10.1002/cmdc.200600294 · Cited by 83 · cited 2×
“Mycro3 (Figure 7) was identified by Kiessling et al. (2007) [109] via high-throughput screening of a library of 1438 pyrazolo [1,5-α] pyrimidines that were built upon the two predecessor compounds, Mycro1 and Mycro2 [110].”
Background
Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation
Mo, H., & Arsenian‐Henriksson, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601418103 · Cited by 81 · cited 6×
“’s [121,122] findings suggest that the three small molecules can elicit a similar biological response by interfering with the Myc pathway at different levels: all three compounds induced apoptosis in Myc overexpressing cells, albeit with different mechanisms of action [121,122].”
BackgroundMethodInfluential
The Impact of Small Molecule Binding on the Energy Landscape of the Intrinsically Disordered Protein C-Myc
Michel, J., & Cuchillo, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041070 · Cited by 76 · cited 1×
“[158], using explicit solvent enhanced sampling meta-dynamics simulations on 10058-F4, reported that 10058-F4 interacts with a Myc402–412 conformational ensemble at multiple different dynamically-formed pockets within the peptide segment, and that the ligand binding was driven by weak and non-specific interactions, bu…”
Method
Targeted Disruption of Myc–Max Oncoprotein Complex by a Small Molecule
Choi, S. H., Mahankali, M., Lee, S. J., Hull, M. V., Petrassi, H. M., Chatterjee, A. K., Schultz, P. G., Jones, K. A., & Shen, W. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00799 · Cited by 75 · cited 4×
“…tissues in a manner similar to Omomyc treatment in healthy tissues [112]. sAJM589 is a novel small molecule Myc inhibitor identified by Choi et al. (2017) [117] from a Gaussia-based PCA-based high-throughput screen of ~400,000 drug-like molecules (Figure 7). sAJM589 is a potent…”
BackgroundInfluential
Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells
Lu, J., Meng, L.-H., Shankavaram, U. T., Zhu, C.-H., Tong, L.-J., Chen, G., Lin, L.-P., Weinstein, J. N., & Ding, J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.02.016 · Cited by 75 · cited 1×
“The synthetically lethal compound dihydroartemisinin (a common metabolite of the highly potent and safe anti-malarial agent, artemisinin) was found to activate the Ser/Thr kinase GSK3β, which in turn phosphorylates and destabilizes Myc [91].”
Background
Recent Progress and Future Potential for Metal Complexes as Anticancer Drugs Targeting G-quadruplex DNA
Zhang, J., Zhang, F., Li, H., Liu, C., Xia, J., Ma, L., Chu, W., Zhang, Z., Chen, C., Li, S., et al. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712800672067 · Cited by 72
Taking on Challenging Targets: Making MYC Druggable
Horiuchi, D., Anderton, B. N., & Goga, A. (2014) · American Society of Clinical Oncology Educational Book · doi:10.14694/edbook_am.2014.34.e497 · Cited by 67 · cited 1×
“However, for many years it has been pessimistically considered “undruggable” [22].”
Background
Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
Stump, S., Mou, T., Sprang, S. R., Natale, N. R., & Beall, H. D. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205584 · Cited by 64
Stabilizers of the Max Homodimer Identified in Virtual Ligand Screening Inhibit Myc Function
Jiang, H., Bower, K. E., Beuscher, A. E., Zhou, B., Bobkov, A. A., Olson, A. J., & Vogt, P. K. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.054858 · Cited by 62 · cited 4×
“[150] identified three main sites, coined “site 1, site 2, and site 3” utilizing both the ordered Max-Max [74] a d Myc-Max [75] X-ray structures to discover in silico specific Max-Max stabilizers that inhibited Myc-Max function ( s described in the Section 3.”
BackgroundInfluential
A 13-Amino Acid Amphipathic α-Helix Is Required for the Functional Interaction between the Transcriptional Repressor Mad1 and mSin3A
Eilers, A. L., Billin, A. N., Liu, J., & Ayer, D. E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32750 · Cited by 62
MYC Cofactors: Molecular Switches Controlling Diverse Biological OutcomesPreprint
Hann, S. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014399 · Cited by 60 · cited 2×
“These domains contain highly conserved modules that provide docking sites for a large number of cofactors that regulate Myc activity and stability [16,17].”
Background
Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation
Jin, S. K., Stover, J. S., Whitby, L. R., Vogt, P. K., & Boger, D. L. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.09.044 · Cited by 59 · cited 1×
“[98] introduced structural modification to the members of the same peptidomimetic library and identified two optimized compounds, Mycmycin-1 and Mycmycin-2, which were shown to specifically inhibit Myc-induced oncogenic transformation having no undesired effect on Jun-driven or unrelated Src protein kinase-driven tran…”
Background
Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma
Soodgupta, D., Pan, D., Cui, G., Senpan, A., Yang, X., Lu, L., Weilbaecher, K. N., Prochownik, E. V., Lanza, G. M., & Tomasson, M. H. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0774-t · Cited by 59 · cited 2×
“(2015) [108] reported nanoparticle targeted-delivery of 10058-F4 as an Sn2 lipase-labile pro-drug in the form of MI1-PD, which showed in vivo efficacy, as it extended survival in a mouse model of metastatic multiple myeloma.”
Background
Disruption of Myc-Max Heterodimerization with Improved Cell-Penetrating Analogs of the Small Molecule 10074-G5
Wang, H., Chauhan, J., Hu, A., Pendleton, K. P., Yap, J. L., Sabato, P. E., Jones, J. W., Perri, M., Yu, J., Cione, E., et al. (2013) · Oncotarget · doi:10.18632/oncotarget.1108 · Cited by 57 · cited 6×
“5 μM for 10058-F4 and 10074-G5, respectively, on growth inhibition of HL-60 human promyelocytic leukemia cells that overexpress Myc due to gene amplification) [100], lack of selectivity, and poor pharmacokinetic behavior as they undergo rapid metabolism resulting in low tumoral concentrations that are insufficient to…”
BackgroundMethodInfluential
Computer-aided drug discovery of Myc-Max inhibitors as potential therapeutics for prostate cancer
Carabet, L. A., Lallous, N., Leblanc, E., Ban, F., Morin, H., Lawn, S. O., Ghaidi, F., Lee, J., Mills, I. G., Gleave, M. E., et al. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.09.023 · Cited by 56 · cited 4×
“The in silico hit-to-lead optimization protocol involving both structure- and ligand-based modeling techniques and consensus scoring computations has been fully described in our study [136].”
BackgroundMethodInfluentialSelf-citation
Intravesical Instillation of c-MYC Inhibitor KSI-3716 Suppresses Orthotopic Bladder Tumor Growth
Jeong, K., Kim, K., Seo, H.-H., Shin, S.-P., Ahn, K.-O., Ji, M.-J., Park, W. S., Kim, I.-H., Lee, S.-J., & Seo, H. K. (2013) · The Journal of Urology · doi:10.1016/j.juro.2013.07.019 · Cited by 55 · cited 5×
“(2014) [124] showed that KSI-3716 blocked Myc-Max binding to target gene promoters and decreased Myc-mediated transcriptional activity at concentrations as low as 1 μM, as well as the expression of target genes, including cyclin D2, CDK4, and hTERT.”
BackgroundInfluential
Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids
Wang, H., Teriete, P., Hu, A., Raveendra-Panickar, D., Pendelton, K., Lazo, J. S., Eiseman, J., Holien, T., Misund, K., Oliynyk, G., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6116 · Cited by 53 · cited 1×
“The developed Myc-Max/DNA disruptors include: natural-occurring compounds, such as celastrol and celastrol-inspired triterpenoids [119]; synthetic α-mimetics, such as JKY-2-169 intentionally engineered to recognize the structurally ordered Myc and hence to disrupt Myc-Max/DNA binding [120]; small molecule inhibitors (…”
Background
G-quadruplex virtual drug screening: A review
Monsen, R. C., & Trent, J. O. (2018) · Biochimie · doi:10.1016/j.biochi.2018.06.024 · Cited by 52
JQ1: a novel potential therapeutic target
Shi, X., Liu, C., Liu, B., Chen, J., Wu, X., & Gong, W. (2018) · Die Pharmazie · doi:10.31083/ph.2018.8480 · Cited by 51
Discovery of Methyl 4′‐Methyl‐5‐(7‐nitrobenzo[ c ][1,2,5]oxadiazol‐4‐yl)‐[1,1′‐biphenyl]‐3‐carboxylate, an Improved Small‐Molecule Inhibitor of c‐Myc–Max Dimerization
Chauhan, J., Wang, H., Yap, J. L., Sabato, P. E., Hu, A., Prochownik, E. V., & Fletcher, S. (2014) · ChemMedChem · doi:10.1002/cmdc.201402189 · Cited by 49 · cited 4×
“3jc48-3 is considered to be one of the most potent, cellular active, and stable Myc inhibitors fr m the classical series developed by the group [100,103,105,106].”
BackgroundInfluential
JQ1: a novel potential therapeutic target.
Shi, X., Liu, C., Liu, B., et al. (2018) · PubMed · doi:10.1691/ph.2018.8480 · Cited by 49 · cited 1×
“In the latter category, JQ1 was the first reported compound to inhibit Myc-associated chromatin remodeling enzyme Brd4 [86], followed by novel BET inhibitors, such as ZEN-3694, which entered clinical trials and demonstrated efficacy in a variety of solid tumors and hematological malignancies, alone or in combination w…”
Background
Discovery of a Natural Product-Like c-myc G-Quadruplex DNA Groove-Binder by Molecular Docking
Ma, D., Chan, D. S., Fu, W. C., He, H., Yang, H., Yan, S., & Leung, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043278 · Cited by 48
Abstract A49: Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC)
Shapiro, G. I., Dowlati, A., LoRusso, P. M., Eder, J. P., Anderson, A., Do, K. T., Kagey, M. H., Sirard, C. A., Bradner, J. E., & Landau, S. B. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-15-a49 · Cited by 47
Coordination of Nutrient Availability and Utilization by MAX- and MLX-Centered Transcription NetworksPreprint
O'Shea, J. M., & Ayer, D. E. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014258 · Cited by 47 · cited 3×
“While Mlx does not associate with Max or Myc family members, it dimerizes with two others partners, MondoA (MLXIP) and ChREBP (MondoB or MLXIPL), which are cytoplasmic-nuclear shuttling proteins whose accumulation in the nucleus is triggered by glucose-derived metabolites [59,71].”
Background
Domain-specific c-Myc ubiquitylation controls c-Myc transcriptional and apoptotic activity
Zhang, Q., Spears, E., Boone, D. N., Li, Z., Gregory, M. A., & Hann, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208334110 · Cited by 46 · cited 1×
“The ARF tumor suppressor antagonizes SKP2-mediated ubiquitination, inhibits Myc transactivation, proliferation, and transformation, and promotes Myc-induced, p53-independent apoptosis [57].”
Background
Overexpression of c-myc is associated with adverse clinical features and worse overall survival in multiple myeloma
Szabo, A. G., Gang, A. O., Pedersen, M. Ø., Poulsen, T. S., Klausen, T. W., & Nørgaard, P. H. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2016.1187275 · Cited by 45 · cited 1×
“[130] reported yet another novel inhibitor, 7594-0035, specifically targeting Myc for the potential treatment of relapsed/refractory multiple myeloma (MM), in which frontline therapy-resistance has been associated with Myc [131,132].”
Background
Pharmacophore-based discovery of triaryl-substituted imidazole as new telomeric G-quadruplex ligand
Chen, S.-B., Tan, J., Ou, T., Huang, S., An, L., Luo, H., Li, D., Gu, L., & Huang, Z. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.12.019 · Cited by 44
NMR-Driven Discovery of Benzoylanthranilic Acid Inhibitors of Far Upstream Element Binding Protein Binding to the Human Oncogene c-myc Promoter
Huth, J. R., Yu, L. P., Collins, I. J., Mack, J. C., Mendoza, R. R., Isaac, B., Braddock, D. T., Muchmore, S. W., Comess, K. M., Fesik, S. W., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0497803 · Cited by 44
MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation
Anderson, S., Poudel, K. R., Roh‐Johnson, M., Brabletz, T., Yu, M., Borenstein‐Auerbach, N., Grady, W., Bai, J., Moens, C. B., Eisenman, R. N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610994113 · Cited by 43
A Pt(ii)–Dip complex stabilizes parallel c-myc G-quadruplex
Wang, J., Lu, K., Xuan, S., Toh, Z., Zhang, D., & Shao, F. (2013) · Chemical Communications · doi:10.1039/c3cc40868j · Cited by 41
Small-molecule inhibitors of c-Myc transcriptional factor suppress proliferation and induce apoptosis of promyelocytic leukemia cell via cell cycle arrest
Jeong, K., Ahn, K.-O., & Yang, C. (2010) · Molecular BioSystems · doi:10.1039/c002534h · Cited by 41 · cited 3×
“The developed Myc-Max/DNA disruptors include: natural-occurring compounds, such as celastrol and celastrol-inspired triterpenoids [119]; synthetic α-mimetics, such as JKY-2-169 intentionally engineered to recognize the structurally ordered Myc and hence to disrupt Myc-Max/DNA binding [120]; small molecule inhibitors (…”
BackgroundMethodInfluential
Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion
Wang, H., Sharma, L., Lu, J. L., Finch, P., Fletcher, S., & Prochownik, E. V. (2015) · Oncotarget · doi:10.18632/oncotarget.4327 · Cited by 41 · cited 1×
“by ATP depletion, neutral lipid accumulation, AMPK (adenosine monophosphate-activated protein kinase) activation, cell-cycle arrest, and apoptosis [96].”
Background
Synergistic Applications of MD and NMR for the Study of Biological Systems
Fisette, O., Lagüe, P., Gagné, S. M., & Morin, S. (2012) · BioMed Research International · doi:10.1155/2012/254208 · Cited by 40 · cited 1×
“MD is the computational method that best complements X-ray and NMR-based techniques that may lack sufficient resolution to fully investigate IDPs, for they cannot reveal the complete dynamic behavior of IDPs in atomistic details, nonetheless experimental structural data, such as NMR chemical shifts, are necessary to e…”
Method
Chemical intervention of the NM23-H2 transcriptional programme onc-MYCvia a novel small molecule
Shan, C., Lin, J., Hou, J., Liu, H., Chen, S.-B., Chen, A.-C., Ou, T., Tan, J., Li, D., Gu, L., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv641 · Cited by 39
Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer
Seo, H. K., Ahn, K.-O., Jung, N.-R., Shin, J., Park, W. S., Lee, K. H., Lee, S.-J., & Jeong, K. (2014) · Oncotarget · doi:10.18632/oncotarget.1545 · Cited by 38 · cited 3×
“Notably, KSI-3716 suppressed gemcitabine-resistant xenograft tumors (KU19-19/GEM) that formed in the presence of as little as 2 mg/kg gemcitabine, and therapeutic potency was augmented by sequential addition of gemcitabine and KSI-3716, suggesting that the sequential combination treatment may benefit bladder cancer pa…”
BackgroundInfluential
Myc Overexpression Enhances Apoptosis Induced by Small Molecules
Mo, H., Vita, M. F., Crespin, M., & Arsenian‐Henriksson, M. (2006) · Cell Cycle · doi:10.4161/cc.5.19.3320 · Cited by 37 · cited 5×
“’s [121,122] findings suggest that the three small molecules can elicit a similar biological response by interfering with the Myc pathway at different levels: all three compounds induced apoptosis in Myc overexpressing cells, albeit with different mechanisms of action [121,122].”
BackgroundInfluential
Both the helix-loop-helix and the leucine zipper motifs of c-Myc contribute to its dimerization specificity with Max.
Davis, L. J., & Halazonetis, T. D. (1993) · PubMed · Cited by 36
Overexpressed max is not oncogenic and attenuates myc-induced lymphoproliferation and lymphomagenesis in transgenic mice.
Lindeman, G. J., Harris, A. W., Bath, M. L., Eisenman, R. N., & Adams, J. M. (1995) · PubMed · Cited by 36
CRD-BP: a c-Myc mRNA stabilizing protein with an oncofetal pattern of expression.
Ioannidis, P., Mahaira, L. G., Papadopoulou, A., Teixeira, M. R., Heim, S., Andersen, J. A., Εvangelou, Ε., Dafni, U. G., Pandis, N., & Trangas, T. T. (2003) · PubMed · Cited by 33
Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates
Han, X., Li, C., Mosher, M. D., Rider, K. C., Zhou, P., Crawford, R. L., Fusco, W. G., Paszczynski, A. J., & Natale, N. R. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.12.056 · Cited by 33
Sin3b Interacts with Myc and Decreases Myc Levels
García‐Sanz, P., Quintanilla, A., Lafita‐Navarro, M. C., Moreno‐Bueno, G., García-Gutiérrez, L., Tabor, V., Varela, I., Shiio, Y., Larsson, L.-G., Portillo, F., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.538744 · Cited by 32 · cited 2×
“repression, as it provides docking sites for components of histone deacetylase repressor complexes, such as SIN3 and HDAC3 [47,48], and MBIV, also important for Myc transcriptional activity and Myc-induced apoptosis.”
Background
Mnt transcriptional repressor is functionally regulated during cell cycle progression
Popov, N., Wahlström, T., Hurlin, P. J., & Arsenian‐Henriksson, M. (2005) · Oncogene · doi:10.1038/sj.onc.1208961 · Cited by 32 · cited 1×
“It has been proposed that Myc f nctions by the relief of Mnt repression [63,64].”
Background
A moving target: structure and disorder in pursuit of Myc inhibitors
Bayliss, R. W., Burgess, S. G., Leen, E. N., & Richards, M. W. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160328 · Cited by 29
Identification of a novel c-Myc inhibitor with antitumor effects on multiple myeloma cells
Yao, R., Sun, X., Xie, Y., Sun, X., Yao, Y., Li, H., Li, Z., Gao, J., & Xu, K. (2018) · Bioscience Reports · doi:10.1042/bsr20181027 · Cited by 25
Preparation of a Kröhnke Pyridine Combinatorial Library Suitable for Solution-Phase Biological Screening
Fujimori, T., Wirsching, P., & Janda, K. D. (2003) · Journal of Combinatorial Chemistry · doi:10.1021/cc0300208 · Cited by 25 · cited 2×
“(2014) [112] within a 220-membered Kröhnke pyridine combinatorial library [113] screened by a fluorescence polarization assay for the inhibition of Myc-Max dimerization (Figure 7).”
Background
The Myc/Max/Mad Transcription Factor Network
Eisenman, R. N. (2006) · Current topics in microbiology and immunology · doi:10.1007/3-540-32952-8 · Cited by 23
Identification of a selective G-quadruplex DNA binder using a multistep virtual screening approach
Hou, J., Chen, S.-B., Zan, L.-P., Ou, T., Tan, J., Luyt, L. G., & Huang, Z. (2014) · Chemical Communications · doi:10.1039/c4cc06951j · Cited by 23 · cited 1×
“Following an incremental fragment-based docking approach that was implemented in the Surflex-DOCK platform [202], Hou et al. (2015) [203] identified a novel MYC G4 stabilizer from a screen of 28,530 compounds from the Chembridge repository against the NMR 1XAV Pu22 structure, rescored to eliminate…”
Method
Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition
Poole, C. J., Zheng, W., Lee, H., Young, D., Lodh, A., Chadli, A., & van Riggelen, J. (2018) · Cancers · doi:10.3390/cancers10110448 · Cited by 22
Hit Identification of a Novel Dual Binder for h‐telo/c‐myc G‐Quadruplex by a Combination of Pharmacophore Structure‐Based Virtual Screening and Docking Refinement
Rocca, R., Costa, G., Artese, A., Parrotta, L., Ortuso, F., Maccioni, E., Pinato, O., Greco, M. L., Sissi, C., Alcaro, S., et al. (2016) · ChemMedChem · doi:10.1002/cmdc.201600053 · Cited by 20 · cited 1×
“Rocca et al. (2016) [204] used a combination of structure-based pharmacophore screening and docking refinement to identify a novel “dual-specificity” G4 stabilizer binding to both h-Telo telomeric and MYC promoter G4s.”
Method

Flagged first, then by citations

2 of the 213 references couldn’t be matched to a known paper.

Sorted by citations

The MYC oncogene — the grand orchestrator of cancer growth and immune evasion
Dhanasekaran, R., Deutzmann, A., Mahauad‐Fernandez, W. D., Hansen, A. S., Gouw, A. M., & Felsher, D. W. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00549-2 · Cited by 1,044
Targeting transcription factors in cancer — from undruggable to reality
Bushweller, J. H. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0196-7 · Cited by 919
Therapeutic targeting of “undruggable” MYC
Llombart, V., & Mansour, M. R. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103756 · Cited by 507
Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy
Han, H., Jain, A. D., Truica, M. I., Izquierdo-Ferrer, J., Anker, J. F., Lysy, B., Sagar, V., Luan, Y., Chalmers, Z. R., Unno, K., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.001 · Cited by 479
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396

See all 175

Authors: Carabet, L. A., Rennie, P. S., & Cherkasov, A.
Affiliations: University of British Columbia (CA)
Corresponding author: Cherkasov, Artem
ORCID: Cherkasov, Artem
Venue: International Journal of Molecular Sciences
Publisher: MDPI AG
Published: 2018-12-29
Volume: 20
Issue: 1
Pages: 120
ISSN: 1422-0067 (ISSN-L)
DOI: 10.3390/ijms20010120
PMC: PMC6337544
OpenAlex: W2907541282
Cited by: 172
References: 213
Citations by year: 2026: 11 · 2025: 23 · 2024: 29 · 2023: 17 · 2022: 23 · 2021: 29 · 2020: 26 · 2019: 14
FWCI: 1.81
Type: journal article
Language: en
Open access: gold
dx.doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: International Journal of Molecular Sciences (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
cIRcle (University of British Columbia) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Open Collections
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
Keywords: c-Myc, MYC inhibitors, undruggable targets, intrinsically disordered proteins, small molecule inhibitors, structure-function relationship, protein-protein interaction, DNA-binding domain, cancer therapy resistance, computer-aided drug design
MeSH terms: Animals, Antineoplastic Agents, Humans, Protein Binding, Proto-Oncogene Proteins c-myc, Quantitative Structure-Activity Relationship, Small Molecule Libraries, Drug Discovery, Molecular Docking Simulation

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Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches

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