Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches
Open accessAbstract
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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Two compounds, VPC-70067 and VPC-70063, were ultimately obtained.
“Two compounds, VPC-70067 (191) and VPC-70063 (192) (Table 3), were ultimately obtained.472”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [472]
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Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC
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“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].”
BackgroundIdentification of the Human c- myc Protein Nuclear Translocation Signal
Dang, C. V., & Lee, W. M. F. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.10.4048-4054.1988 · Cited by 304 · see citing works
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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 299 · cited 1× · see citing works
“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].”
BackgroundRapid 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 297 · see citing works
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“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].”
BackgroundStrategies 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 295 · see citing works
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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 290 · see citing works
Targeting MYC Expression through G-Quadruplexes
Brooks, T., & Hurley, L. (2010) · Genes & cancer · doi:10.1177/1947601910377493 · Cited by 290 · see citing works
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× · see citing works
“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].”
BackgroundInfluentialSurflex-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 284 · cited 1× · see citing works
“The Surflex molecular docking [133] module in the Sybyl-X2.”
MethodBahram, F., von der Lehr, N., Cetinkaya, C., & Larsson, L. (2000) · Blood · doi:10.1182/blood.v95.6.2104 · Cited by 283 · see citing works
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 280 · see citing works
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 · see citing works
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× · see citing works
“, MAPK, mTORC1 and FOXO3a) [30], and inhibitors of Myc chromatin remodeling and transcription of BET bromodomain proteins [85].”
BackgroundMathad, R. I., Hatzakis, E., Dai, J., & Yang, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr612 · Cited by 242 · see citing works
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× · see citing works
“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].”
BackgroundFunction 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 238 · cited 7× · see citing works
“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].”
BackgroundInfluentialBrd4 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 237 · cited 1× · see citing works
“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…”
BackgroundThe 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 237 · see citing works
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 232 · cited 6× · see citing works
“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].”
BackgroundInfluentialTherapeutic Strategies to Inhibit MYCPreprint
McKeown, M. R., & Bradner, J. E. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014266 · Cited by 226 · cited 1× · see citing works
“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].”
BackgroundDesign 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× · see citing works
“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].”
BackgroundMyc 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 223 · see citing works
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 · see citing works
Conacci‐Sorrell, M., Ngouenet, C., & Eisenman, R. N. (2010) · Cell · doi:10.1016/j.cell.2010.06.037 · Cited by 219 · see citing works
The c‐myc Promoter: Still MysterY and Challenge
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“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].”
BackgroundInfluentialUse 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 · see citing works
Yuan, Y., Pei, J., & Lai, L. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319120019 · Cited by 199 · see citing works
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 · see citing works
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× · see citing works
“This inconsistent behavior possibly reflected multiple binding modes of singly or dual substituted analogs to different conformations of the intrinsically disordered Myc monomer [104].”
BackgroundFisher, F. A., & Goding, C. R. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05503.x · Cited by 191 · cited 3× · see citing works
“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…”
BackgroundInfluentialPREDITOR: 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× · see citing works
“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].”
MethodFollis, 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 · see citing works
Baudino, T. A., & Cleveland, J. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.3.691-702.2001 · Cited by 182 · cited 2× · see citing works
“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].”
BackgroundFranke, 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 176 · see citing works
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 · see citing works
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 175 · cited 1× · see citing works
“[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].”
BackgroundThakur, 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 · see citing works
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× · see citing works
“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].”
BackgroundVisualization 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× · see citing works
“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].”
BackgroundThe 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 · see citing works
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 166 · see citing works
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 163 · see citing works
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 · see citing works
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× · see citing works
“, AP4, homologous bHLHLZ transcription factor) into a canonical class B E-box binding protein [79].”
BackgroundSmall-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 153 · cited 3× · see citing works
“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].”
BackgroundInhibitor 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× · see citing works
“(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).”
BackgroundInfluentialSelective 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 148 · cited 2× · see citing works
“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].”
BackgroundDesign 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 135 · see citing works
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 129 · cited 3× · see citing works
“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].”
BackgroundInfluentialBinding 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× · see citing works
“Non-canonical sequences, such as 5′-CACGCG-3′ and 5′-CATGGC-3′, represent low-affinity Myc-Max binding sites [21].”
BackgroundCastell, 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 126 · cited 2× · see citing works
“[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…”
BackgroundMethodMyc 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 125 · cited 2× · see citing works
“These domains contain highly conserved modules that provide docking sites for a large number of cofactors that regulate Myc activity and stability [16,17].”
BackgroundFelsenstein, 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 125 · see citing works
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 123 · cited 2× · see citing works
“, 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].”
BackgroundGuo, 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× · see citing works
“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].”
BackgroundIntegrative 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 122 · see citing works
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 118 · see citing works
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× · see citing works
“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…”
BackgroundStructure-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 115 · cited 7× · see citing works
“[25] provided a useful strategy for SBDD targeting intrinsically disordered proteins (IDPs) while also suggesting”
BackgroundMethodInfluentialBarfeld, 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 114 · see citing works
Self-citationOu, 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 · see citing works
Jin, F., Chen, Y., Lai, L., & Liu, Z. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003249 · Cited by 108 · cited 4× · see citing works
“[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…”
BackgroundMethodInfluentialFacchini, 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 107 · cited 1× · see citing works
“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].”
BackgroundMyc-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× · see citing works
“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.”
BackgroundDuan, 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 · see citing works
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 · see citing works
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× · see citing works
“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].”
BackgroundInfluentialHu, 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 · see citing works
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 100 · see citing works
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 97 · see citing works
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 96 · see citing works
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 · see citing works
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× · see citing works
“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].”
BackgroundMYC Modulation around the CDK2/p27/SKP2 Axis
Hydbring, P., Castell, A., & Larsson, L. (2017) · Genes · doi:10.3390/genes8070174 · Cited by 90 · see citing works
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× · see citing works
“It has been proposed that Myc f nctions by the relief of Mnt repression [63,64].”
BackgroundOrdering 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 84 · cited 1× · see citing works
“The Mga member of the extended network has been suggested to act as a tumor suppressor, with inactivating mutations detected in leukemia [61].”
BackgroundPharmacophore 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× · see citing works
“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].”
BackgroundInfluentialTherapeutic 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 83 · cited 6× · see citing works
“(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).”
BackgroundResultInfluentialSelective 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× · see citing works
“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].”
BackgroundMo, H., & Arsenian‐Henriksson, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601418103 · Cited by 80 · cited 6× · see citing works
“’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].”
BackgroundMethodInfluentialTargeting 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 79 · cited 5× · see citing works
“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].”
BackgroundInfluentialTargeted 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× · see citing works
“…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…”
BackgroundInfluentialLu, 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× · see citing works
“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].”
BackgroundMichel, J., & Cuchillo, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041070 · Cited by 74 · cited 1× · see citing works
“[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…”
MethodZhang, 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 · see citing works
Brewer, G., & Ross, J. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.4.1697-1708.1988 · Cited by 71 · cited 1× · see citing works
“The first is translation-independent, involving poly(A) tail shortening that is regulated by AU-rich sequences in the 3′ untranslated region [34,35].”
BackgroundTaking 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× · see citing works
“However, for many years it has been pessimistically considered “undruggable” [22].”
BackgroundCrystal 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 63 · see citing works
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× · see citing works
“[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.”
BackgroundInfluentialEilers, 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 · see citing works
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× · see citing works
“These domains contain highly conserved modules that provide docking sites for a large number of cofactors that regulate Myc activity and stability [16,17].”
BackgroundSmall 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× · see citing works
“[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…”
BackgroundSoodgupta, 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× · see citing works
“(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.”
BackgroundWang, 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× · see citing works
“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…”
BackgroundMethodInfluentialIntravesical 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× · see citing works
“(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.”
BackgroundInfluentialComputer-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 54 · cited 4× · see citing works
“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-citationDirect 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× · see citing works
“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 (…”
BackgroundG-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 · see citing works
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 · see citing works
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× · see citing works
“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].”
BackgroundInfluentialJQ1: 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× · see citing works
“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…”
BackgroundShapiro, 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 · see citing works
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× · see citing works
“The ARF tumor suppressor antagonizes SKP2-mediated ubiquitination, inhibits Myc transactivation, proliferation, and transformation, and promotes Myc-induced, p53-independent apoptosis [57].”
BackgroundDiscovery 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 46 · see citing works
O'Shea, J. M., & Ayer, D. E. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014258 · Cited by 46 · cited 3× · see citing works
“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].”
BackgroundSzabo, 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× · see citing works
“[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].”
BackgroundPharmacophore-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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Jeong, K., Ahn, K.-O., & Yang, C. (2010) · Molecular BioSystems · doi:10.1039/c002534h · Cited by 41 · cited 3× · see citing works
“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 (…”
BackgroundMethodInfluentialStructurally 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× · see citing works
“by ATP depletion, neutral lipid accumulation, AMPK (adenosine monophosphate-activated protein kinase) activation, cell-cycle arrest, and apoptosis [96].”
BackgroundChemical 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 · see citing works
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× · see citing works
“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…”
BackgroundInfluentialMyc 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× · see citing works
“’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].”
BackgroundInfluentialSynergistic 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 37 · cited 1× · see citing works
“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…”
MethodDavis, L. J., & Halazonetis, T. D. (1993) · PubMed · Cited by 36 · see citing works
Lindeman, G. J., Harris, A. W., Bath, M. L., Eisenman, R. N., & Adams, J. M. (1995) · PubMed · Cited by 36 · see citing works
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 33 · cited 1× · see citing works
“It has been proposed that Myc f nctions by the relief of Mnt repression [63,64].”
BackgroundCRD-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 · see citing works
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 · see citing works
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× · see citing works
“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.”
BackgroundA 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 · see citing works
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 · see citing works
Fujimori, T., Wirsching, P., & Janda, K. D. (2003) · Journal of Combinatorial Chemistry · doi:10.1021/cc0300208 · Cited by 25 · cited 2× · see citing works
“(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).”
BackgroundThe 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 · see citing works
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× · see citing works
“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…”
MethodTargeting 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 · see citing works
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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 1,010 · see citing works
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 · see citing works
Therapeutic targeting of “undruggable” MYC
Llombart, V., & Mansour, M. R. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103756 · Cited by 483 · see citing works
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 461 · see citing works
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 citing works
Biomolecular Condensates and Cancer
Boija, A., Klein, I. A., & Young, R. A. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.12.003 · Cited by 320 · see citing works
Serine, glycine and one‑carbon metabolism in cancer (Review)
Pan, S., Fan, M., Liu, Z., Li, X., & Wang, H. (2020) · International Journal of Oncology · doi:10.3892/ijo.2020.5158 · Cited by 227 · see citing works
Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy
Carter, J. L., Hege-Hurrish, K., Yang, J., Kalpage, H. A., Su, Y., Edwards, H. J., Hüttemann, M., Taub, J. W., & Ge, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00361-x · Cited by 223 · see citing works
“Though promising in vitro, in vivo studies with this inhibitor failed due to poor PK and bioavailability.(257) Fortunately, it has been a useful research tool for elucidating the vast control of c-Myc on different aspects of cancer, including AML.”
BackgroundNew insights into protein–protein interaction modulators in drug discovery and therapeutic advance
Nada, H., Choi, Y., Kim, S.-D., Jeong, K. S., Meanwell, N. A., & Lee, K. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02036-3 · Cited by 233 · see citing works
“247,248 251 However, the approach of stabilizing Max homodimers is associated with unintended consequences on other Max functions.”
MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies
Ahmadi, S. E., Rahimi, S., Zarandi, B., Chegeni, R., & Safa, M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01111-4 · Cited by 211 · see citing works
Fatma, H., Maurya, S., & Siddique, H. R. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.11.008 · Cited by 180 · see citing works
Mission Possible: Advances in MYC Therapeutic Targeting in Cancer
Allen-Petersen, B. L., & Sears, R. C. (2019) · BioDrugs · doi:10.1007/s40259-019-00370-5 · Cited by 143 · see citing works
C-myc Contributes to Malignancy of Lung Cancer: A Potential Anticancer Drug Target
Pithi Chanvorachote, B., Sriratanasak, N., & Nonpanya, N. (2020) · Anticancer Research · doi:10.21873/anticanres.13990 · Cited by 103 · see citing works
MYC and therapy resistance in cancer: risks and opportunities
Donati, G., & Amati, B. B. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13319 · Cited by 99 · see citing works
The long journey to bring a Myc inhibitor to the clinic
Whitfield, J. R., & Soucek, L. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202103090 · Cited by 97 · see citing works
Human MYC G-quadruplex: From discovery to a cancer therapeutic target
Wang, W., Hu, S., Gu, Y., Yan, Y., Stovall, D. B., Li, D., & Sui, G. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188410 · Cited by 77 · see citing works
Zhang, H., Sun, Y., Wang, Z., Huang, X., Tang, L., Jiang, K., & Jin, X. (2024) · Nature Communications · doi:10.1038/s41467-024-49105-3 · Cited by 75 · see citing works
“MYC is overexpressed in approximately 70% of malignancies, induces tumor progression and is associated with poor prognosis 47 – 49 .”
Transcription Factors That Govern Development and Disease: An Achilles Heel in Cancer
Huilgol, D., Venkataramani, P., Nandi, S., & Bhattacharjee, S. (2019) · Genes · doi:10.3390/genes10100794 · Cited by 70 · see citing works
Control of cell metabolism by the epidermal growth factor receptor
Orofiamma, L. A., Vural, D., & Antonescu, C. N. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119359 · Cited by 69 · see citing works
Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment
Frattaruolo, L., Brindisi, M., Curcio, R., Marra, F., Dolce, V., & Cappello, A. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176014 · Cited by 66 · see citing works
“This factor is able to integrate signals from different pathways, as well as modulating the expression of genes involved in metabolism, proliferation, apoptosis, and neoplastic transformation [134].”
BackgroundHolmes, A. G., Parker, J. B., Sagar, V., Truica, M. I., Soni, P. N., Han, H., Schiltz, G. E., Abdulkadir, S. A., & Chakravarti, D. (2022) · Science Advances · doi:10.1126/sciadv.abh3635 · Cited by 61 · see citing works
“Several small-molecule inhibitors (e.g., 10075-G5 and 10058-F4) disrupt MYC/MAX dimerization and have been shown to reduce MYC activity ( 9 , 10 ).”
Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma
Traweek, R. S., Cope, B. M., Roland, C. L., Keung, E. Z.-Y., Nassif, E. F., & Erstad, D. J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1006959 · Cited by 61 · see citing works
Specific Recognition of Promoter G-Quadruplex DNAs by Small Molecule Ligands and Light-up Probes
Dhamodharan, V., & Pradeepkumar, P. I. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00475 · Cited by 60 · see citing works
“because it is an intrinsically disordered protein that lacks a defined enzymatic site or binding pocket, and thus it is not amenable to small-molecule inhibition.(48) In this context, c-MYC G4 provides an attractive target for small molecules to regulate its expression.”
BackgroundLi, Z., Xie, Y., Deng, M., Zhu, L., Wu, X., Li, G., Shi, N.-X., Wen, C., Huang, W., Duan, Y., et al. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.11.006 · Cited by 55 · see citing works
Targeting Myc-driven stress addiction in colorectal cancer
Saeed, H., Leibowitz, B. J., Zhang, L., & Yu, J. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2023.100963 · Cited by 53 · see citing works
Carabet, L. A., Leblanc, E., Lallous, N., Morin, H., Ghaidi, F., Lee, J., Rennie, P. S., & Cherkasov, A. R. (2019) · Molecules · doi:10.3390/molecules24040763 · Cited by 53 · see citing works
Self-citationChen, P., Yang, W., Hong, T., Miyazaki, T., Dirisala, A., Kataoka, K., & Cabral, H. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121748 · Cited by 51 · see citing works
Demystifying the Druggability of the MYC Family of Oncogenes
Karadkhelkar, N. M., Lin, M., Eubanks, L. M., & Janda, K. D. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c12732 · Cited by 50 · see citing works
Role of condensates in modulating DNA repair pathways and its implication for chemoresistance
Dall’Agnese, G., Dall’Agnese, A., Banani, S. F., Codrich, M., Malfatti, M. C., Antoniali, G., & Tell, G. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104800 · Cited by 47 · see citing works
“Although no clinically approved drug has been shown to act by specifically targeting cancer-promoting condensates thus far, studies showing the achievability of this option have been published (141, 154, 155).”
BackgroundNameki, R. A., Chang, H. S. Y., Reddy, J., Corona, R. I., & Lawrenson, K. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107722 · Cited by 47 · see citing works
Batsika, C. S., Mantzourani, C., Gkikas, D., Kokotou, M. G., Mountanea, O. G., Kokotos, C. G., Politis, P. K., & Kokotos, G. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02058 · Cited by 45 · see citing works
MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products
Chan, K. I., Zhang, S., Li, G., Xu, Y., Cui, L., Wang, Y., Su, H., Tan, W., & Zhong, Z. (2024) · Aging and Disease · doi:10.14336/ad.2023.0520 · Cited by 45 · see citing works
Lu, W., Yang, C., He, H., & Liu, H. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.41230 · Cited by 43 · see citing works
“However, it is a challenge to directly targeting c-Myc in the developing c-Myc inhibitors owing to its undruggable protein structure [60, 61].”
BackgroundRadaeva, M., Ton, A., Hsing, M., Ban, F., & Cherkasov, A. R. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.07.018 · Cited by 44 · see citing works
Self-citationAssessment of biochemical recurrence of prostate cancer (Review)
Lin, X., Kapoor, A., Gu, Y. J., Chow, M. J., Xu, H., Major, P. P., & Tang, D. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4893 · Cited by 40 · see citing works
“MYC plays multiple roles in tumorigenesis, which includes the regulation of cancer metabolism (36,37).”
Jung, J. H., Lee, H., Kim, J., Sim, D. Y., Im, E., Kim, S., Chang, S., & Kim, S. (2020) · Cells · doi:10.3390/cells9040985 · Cited by 40 · see citing works
“Accumulating evidence reveals that overabundance and mutations of the Myc family comprising of c-Myc, N-Myc and L-Myc are shown in several cancers [32].”
BackgroundProtein homodimer sequestration with small molecules: Focus on PD-L1
Bailly, C., & Vergoten, G. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113821 · Cited by 38 · see citing works
Liu, W., Chen, L., Yin, D., Yang, Z., Feng, J., Sun, Q., Lai, L., & Guo, X. (2023) · Nature Communications · doi:10.1038/s41467-023-41018-x · Cited by 37 · see citing works
MYC the oncogene from hell: Novel opportunities for cancer therapy
Papadimitropoulou, A., Makri, M., & Zoidis, G. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116194 · Cited by 38 · see citing works
Targeting MYC at the intersection between cancer metabolism and oncoimmunology
Venkatraman, S., Balasubramanian, B., Thuwajit, C., Meller, J., Tohtong, R., & Chutipongtanate, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1324045 · Cited by 38 · see citing works
The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer
Lee, H. Y., Son, S. W., Moeng, S., Choi, S. Y., & Park, J. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020627 · Cited by 35 · see citing works
Molecular landscape of c-Myc signaling in prostate cancer: A roadmap to clinical translation
Faskhoudi, M. A., Molaei, P., Sadrkhanloo, M., Orouei, S., Hashemi, M., Bokaie, S., Rashidi, M., Entezari, M., Zarrabi, A., Hushmandi, K., et al. (2022) · Pathology - Research and Practice · doi:10.1016/j.prp.2022.153851 · Cited by 36 · see citing works
Targeting MYC: From understanding its biology to drug discovery
Ross, J., Miron, C. E., Plescia, J., LaPlante, P., McBride, K. M., Moitessier, N., & Möröy, T. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113137 · Cited by 34 · see citing works
Ahmed, S. S., Rahman, M. O., Alqahtani, A. S., Sultana, N., Almarfadi, O. M., Ali, M. A., & Lee, J. (2022) · Toxicology Reports · doi:10.1016/j.toxrep.2022.12.007 · Cited by 34 · see citing works
Gene Transactivation and Transrepression in MYC-Driven Cancers
Scafuro, M., Capasso, L., Carafa, V., Altucci, L., & Nebbioso, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073458 · Cited by 34 · see citing works
Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex
Feris, E. J., Hinds, J. W., & Cole, M. D. (2019) · PLOS ONE · doi:10.1371/journal.pone.0225784 · Cited by 29 · see citing works
“Since MYC has no inherent enzymatic activity, it is sometimes thought to be “undruggable” [18,19].”
BackgroundSingh, A. K., Kumar, A., Kumar, P., Nayak, N., Bhardwaj, T., Giri, R., & Garg, N. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100903 · Cited by 32 · see citing works
“Myc amplification has been reported to various cancers, and its aberrant expression has been reported in various cancers displaying the worst prognosis (6).”
BackgroundInfluentialA novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma
Cheung, B. B., Kleynhans, A., Mittra, R., Kim, P. Y., Holien, J. K., Nagy, Z. S., Ciampa, O. C., Seneviratne, J. A., Mayoh, C., Raipuria, M., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01712-w · Cited by 30 · see citing works
“functional MYC domains or deep protein ‘pockets’ for drug design [3].”
BackgroundSynthetic lethality: A promising therapeutic strategy for hepatocellular carcinoma
Tang, L., Chen, R., & Xu, X. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.02.016 · Cited by 29 · see citing works
The many lives of Myc in the pancreatic β-cell
Rosselot, C., Baumel-Alterzon, S., Li, Y., Brill, G., Lambertini, L., Katz, L. S., Lu, G., Garcı́a-Ocaña, A., & Scott, D. K. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011149 · Cited by 30 · see citing works
“At the protein level, Myc stability is controlled by multiple ubiquitin ligases, resulting in extremely short half-life of around 20–30 min (62).”
BackgroundLong, H., Hou, Y., Li, J., Song, C., & Ge, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076816 · Cited by 27 · see citing works
McAnulty, J., & DiFeo, A. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249486 · Cited by 27 · see citing works
“Agents that inhibit Myc / Max from binding DNA have also been pursued, although they lack in vivo data and specificity towards Myc / Max [117].”
Senapedis, W. T., Gallagher, K. M., Figueroa, E., Farelli, J. D., Lyng, R., Hodgson, J., O’Donnell, C. W., Newman, J. V., Pacaro, M., Siecinski, S. K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52202-y · Cited by 24 · see citing works
“…oncogene by epigenome modulation using dCas9 molecular tools has already been demonstrated in two works (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929158/ IGD was targeted by dCas9-DNMT3A-3L; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441141/ ( MYC promoter was targeted by dCasX - KRAB”
Quantitative analysis of the human ovarian carcinoma mitochondrial phosphoproteome
Li, N., Qian, S., Li, B., & Zhan, X. (2019) · Aging · doi:10.18632/aging.102199 · Cited by 23 · see citing works
“The major oncogenic mechanisms of c-MYC are related to promotion of cell cycle, drug resistance, reprogramming of cell metabolism, and rapid proliferation [23].”
BackgroundZhang, J., Yang, P., Liu, D., Gao, M., Wang, J., Yu, T., Zhang, X., & Liu, Y. (2021) · Burns & Trauma · doi:10.1093/burnst/tkab031 · Cited by 23 · see citing works
“Although we found that 10058-F4 or OSMI-4 promoted wound healing in diabetic rats, there is still a long way to go before their clinical application due to the lack of cell selectivity [37].”
BackgroundHu, A., Chen, G., Bao, B., Guo, Y., Li, D., Wang, X., Wang, J., Li, Q., Zhou, Y., Gao, H., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1235 · Cited by 22 · see citing works
MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation
Boyd, S. R., Chamakuri, S., Trostle, A. J., Chen, H., Liu, Z., Jain, A., Wang, J., Malovannaya, A., & Young, D. W. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.4c00864 · Cited by 21 · see citing works
lncRNAs as Potential Targets in Small Cell Lung Cancer: MYC -dependent Regulation
Tokgün, O., Tokgün, P. E., İnci, K., & Akça, H. (2020) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520620666200721130700 · Cited by 21 · see citing works
Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer
Ton, A., Singh, K., Morin, H., Ban, F., Leblanc, E., Lee, J., Lallous, N., & Cherkasov, A. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218277 · Cited by 21 · see citing works
Self-citationTargeting MYC: Multidimensional regulation and therapeutic strategies in oncology
Duan, Y., Liu, Z., Wang, Q., Zhang, J., Liu, J., Zhang, Z., & Li, C. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101435 · Cited by 21 · see citing works
“13 Due to the inherent disordered structure of the MYC protein, the design of directly targeting MYC is challenging, but it is no longer deemed as an undruggable target.”
Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution
Sodir, N. M., Pellegrinet, L., Kortlever, R. M., Campos, T., Kwon, Y.-W., Kim, S., Garcia, D. A., Perfetto, A., Anastasiou, P., Swigart, L. B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34079-x · Cited by 20 · see citing works
Šereš, M., Spacayova, K., Sulová, Z., Špaldová, J., Breier, A., & Pavlíková, L. (2025) · Cancers · doi:10.3390/cancers17020248 · Cited by 26 · see citing works
Drug discovery of small molecules targeting the higher-order hTERT promoter G-quadruplex
Monsen, R. C., Maguire, J. M., DeLeeuw, L. W., Chaires, J. B., & Trent, J. O. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270165 · Cited by 19 · see citing works
“While this has energized research targeting the promoter G4s of “undruggable” proteins [12], the issue of ligand specificity remains [10, 13, 14].”
Li, F., Yu, J., Pan, T., Feng, H., Li, J., Yu, B., Fan, Z., Sang, Q., Chen, M., Zang, M., et al. (2023) · Advanced Science · doi:10.1002/advs.202303091 · Cited by 19 · see citing works
NCAPG2 promotes prostate cancer malignancy and stemness via STAT3/c-MYC signaling
Zhang, E., Chen, Z., Liu, W., Lin, L., Wu, L., Guan, J., Wang, J., Kong, C., Bi, J., & Zhang, M. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-023-04834-9 · Cited by 18 · see citing works
“Nonetheless, owing to the intrinsically unstable conformations and essential physiological function of c-MYC, direct inhibition of c-MYC with small-molecule drugs still remains challenging [51, 52].”
BackgroundTon, A.-T., Foo, J., Singh, K., Lee, J., Kalyta, A., Morin, H., Perez, C., Ban, F., Leblanc, E., Lallous, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052588 · Cited by 17 · see citing works
Self-citationEngineering L7Ae for RNA-Only Delivery Kill Switch Targeting CMS2 Type Colorectal Cancer Cells
Yang, J., & Ding, S. (2021) · ACS Synthetic Biology · doi:10.1021/acssynbio.0c00612 · Cited by 16 · see citing works
Bromodomain Inhibitor JQ1 Provides Novel Insights and Perspectives in Rhabdomyosarcoma Treatment
Marchesi, I., Fais, M., Fiorentino, F., Bordoni, V., Sanna, L., Zoroddu, S., & Bagella, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073581 · Cited by 15 · see citing works
Negri, A., Marozzi, M., Trisciuoglio, D., Rotili, D., Mai, A., & Rizzi, F. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2022.2163242 · Cited by 15 · see citing works
Civenni, G., Albino, D., Shinde, D. A., Vázquez, R., Merulla, J., Kokanovic, A., Mapelli, S. N., Carbone, G. M., & Catapano, C. V. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00385 · Cited by 15 · see citing works
“Targeting upstream regulators or downstream effectors of Myc is also a valid approach (100, 102).”
BackgroundOronsky, B. T., Cabrales, P., Caroen, S. Z., Guo, X., Scribner, C. L., Oronsky, A. L., & Reid, T. R. (2021) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1876025 · Cited by 15 · see citing works
“lung carcinomas, and neuroblastoma, among others, which has previously been categorized as ‘undruggable’[21].”
BackgroundThe Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions
Nirala, B. K., & Yustein, J. T. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl37304 · Cited by 14 · see citing works
“MYC is intrinsically disordered, lacking a well-defined hydrophobic pocket or groove suitable for high-affinity binding by low molecular weight compounds [11,43].”
Phase separation drives tumor pathogenesis and evolution: all roads lead to Rome
Gu, X., Zhuang, A., Yu, J., Chai, P., Jia, R., & Ruan, J. (2022) · Oncogene · doi:10.1038/s41388-022-02195-z · Cited by 14 · see citing works
Geng, X., Zhang, Y., Li, S.-H., Liu, L., Yao, R., Liu, L., & Gao, J. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.134673 · Cited by 14 · see citing works
Gold‐Based Pharmacophore Inhibits Intracellular MYC Protein
Ofori, S., Gukathasan, S., & Awuah, S. G. (2020) · Chemistry - A European Journal · doi:10.1002/chem.202004962 · Cited by 14 · see citing works
Triple-negative Breast Cancer: Identification of circRNAs With Efficacy in PreclinicalIn VivoModels
Weidle, U. H., & Birzele, F. (2023) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20368 · Cited by 14 · see citing works
Sriratanasak, N., Petsri, K., Laobuthee, A., Wattanathana, W., Vinayanuwattikun, C., Luanpitpong, S., & Pithi Chanvorachote, B. (2020) · Molecular Pharmacology · doi:10.1124/mol.120.119719 · Cited by 14 · see citing works
“, 2017) and has been linked to almost every aspect of the oncogenic process, including orchestrating uncontrolled tumor growth and proliferation, immortalization, escape from immune surveillance, and rendering treatment resistance (Carabet et al., 2018; Zahavi andWeiner, 2019).”
BackgroundSLC35B4 Stabilizes c-MYC Protein by O-GlcNAcylation in HCC
Jiang, T., Yang, J., Yang, H.-H., Chen, W., Ji, K., Xu, Y., & Yu, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.851089 · Cited by 14 · see citing works
Functional inhibition of c-Myc using novel inhibitors identified through “hot spot” targeting
Singh, A. K., Kumar, P., Sarvagalla, S., Bharadwaj, T., Nayak, N., Coumar, M. S., Giri, R., & Garg, N. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101898 · Cited by 14 · see citing works
“The c-Myc/ MAX heterodimer is considered a hot target for cancer therapeutics as it is linked to nearly 75% of human cancer showing aggressive nature and resistance toward available chemotherapy (17, 18).”
BackgroundElhasasna, H., Khan, R., Bhanumathy, K. K., Vizeacoumar, F. S., Walke, P., Bautista, M., Dahiya, D. K., Maranda, V., Patel, H. M., Amrutha, B., et al. (2022) · Cells · doi:10.3390/cells11142246 · Cited by 13 · see citing works
RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5
Lee, H., Jung, J. H., Ko, H. M., Park, H., Segall, A. M., Sheffmaker, R. L., Wang, J., Frey, W. D., Pham, N., Wang, Y., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308292120 · Cited by 13 · see citing works
“Amplification of the c - Myc - encoding gene is correlated with poor clinical outcome and tumor aggres-siveness (11–14).”
BackgroundKhalid, K. M., Ratnayake, W. S., Apostolatos, C., & Acevedo-Duncan, M. E. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2023.1213715 · Cited by 12 · see citing works
“…(7). c-Myc is reported to be the center of multiple pathways, and it plays a pivotal role in cell proliferation, survival, invasion, and the apoptosis in ccRCC. MYC overexpression occurs rarely due to a direct mutation, rather, it is typically the result of upstream oncogenic signaling (8, 9).”
BackgroundYuan, X., Shao, Y.-C., Guan, X.-Q., Liu, Q., Chu, M.-F., Yang, Z., Li, H., Zhao, S., Tian, Y., Zhang, J., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2024.119716 · Cited by 13 · see citing works
Zhao, C., Zhao, F., Yang, L., Wang, Y., Wang, H., Fang, F., Zuo, H., Li, Z., He, G., Zhan, W., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00272 · Cited by 13 · see citing works
Kant, R., Yang, M., Tseng, C.-H., Yen, C., Li, W.-Y., Tyan, Y., Chen, M., Tzeng, C., Chen, W.-C., You, K., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00093 · Cited by 13 · see citing works
Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target
Sias, F., Zoroddu, S., Migheli, R., & Bagella, L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051973 · Cited by 12 · see citing works
“…It has been found to in fl uence nearly all key aspects of cancer: it promotes angiogenesis, facilitates communication with the tumor microenvironment (TME), suppresses the immune system’s ability to fi ght tumors, and even contributes to resistance against many standard therapies (Figure 4) [16–18].”
Inchworm stepping of Myc-Max heterodimer protein diffusion along DNA
Dai, L., & Yu, J. H. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.08.004 · Cited by 12 · see citing works
Yu, Q., Wang, P., Yang, L., Wu, Z., Li, S., Xu, Y., Wu, B., Ma, A., Gan, X., & Xu, R. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109134 · Cited by 12 · see citing works
Yuan, D., Li, G., Yu, L., Jiang, Y., Shi, Y., Chen, Q., Ma, X., Pham, L. V., Young, K. H., Deng, M., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.618908 · Cited by 11 · see citing works
“To circumvent this dilemma, a series of alternative therapeutic avenues are emerging to disrupt the MYC signaling and subsequently to antagonize its oncogenic activity (24, 25).”
BackgroundPerspectives on drug discovery strategies based on IDPs
Fuertes, G., Nevola, L., & Esteban-Martín, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816348-1.00009-0 · Cited by 11 · see citing works
Transcriptional regulation of MYC through G-quadruplex structures
Balaratnam, S., & Schneekloth, J. S. (2020) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2020.05.002 · Cited by 12 · see citing works
Gonçalves, C. D. N., da Rocha, M. N., & Marinho, E. S. (2025) · In Silico Research in Biomedicine · doi:10.1016/j.insi.2025.100164 · Cited by 10 · see citing works
Zhang, Y., Cai, J., Hosmane, N. S., & Zhu, Y. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116841 · Cited by 10 · see citing works
MYC alterations in multiple myeloma: Genetic insights and prognostic impact
Cristobal‐Vargas, S., Cuadrado, M., & Gutierrez, N. C. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101177 · Cited by 12 · see citing works
Ma, T. P., Izrael-Tomasevic, A., Mroue, R. M., Budayeva, H. G., Malhotra, S., Raisner, R. M., Evangelista, M., Rose, C. M., Kirkpatrick, D. S., & Yu, K. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00703 · Cited by 10 · see citing works
The MYCN 5′ UTR as a therapeutic target in neuroblastoma
Volegova, M. P., Brown, L. E., Banerjee, U., Dries, R., Sharma, B., Kennedy, A. L., Porco, J. A. J., & George, R. E. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114134 · Cited by 9 · see citing works
Gu, K. J., May, H. A., & Kang, M. H. (2024) · Frontiers in Bioscience-Scholar · doi:10.31083/j.fbs1603015 · Cited by 9 · see citing works
“However, the results of these in vitro studies failed to be replicated in vivo because of low bioavailability and poor pharmacokinetics [17].”
BackgroundInverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers
Chareddy, Y. S., Huggins, H. P., Sahoo, S. S., Stanland, L. J., Gutierrez-Ford, C., Whately, K. M., Edatt, L., Azam, S. H., Fleming, M. C., Im, J., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci187204 · Cited by 11 · see citing works
Mao, S., Zhang, X., Zhao, Y., Li, X., Wang, Z., Zhou, P., Wang, Z., Zhang, X., Hu, X., Huang, G., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07333-1 · Cited by 9 · see citing works
“The c-MYC protein (439 amino acids) comprises an N-terminal transactivation domain (TAD), conserved MYC homology boxes (MBs) that mediate PPIs with cofactors, and a C-terminal DNA-binding domain [148, 149].”
Xie, Y., Zhang, W., Guo, L., Kril, L. M., Begley, K. L., Sviripa, V. M., Chen, X., Liu, X., Lee, E. Y., He, D., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-1017 · Cited by 10 · see citing works
- 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)
- 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
- 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
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Pathology and Forensic Medicine › 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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