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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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Figures

Figure 1 40 years of Myc research. Increase in the number of publications available in NCBI PubMed on Myc in general (blue), Myc in cancer (orange), and Myc inhibition (green) from 1979 to 2018.
Figure 1 40 years of Myc research. Increase in the number of publications available in NCBI PubMed on Myc in general (blue), Myc in cancer (orange), and Myc inhibition (green) from 1979 to 2018.CC BY · PubMed Central
Figure 2 Structure of MYC gene and protein: functional domains and interactors. (Top) MYC locus. (Middle) MYC gene organization. (Bottom) Myc protein domains organization. A variety of proteins that regulate Myc activity and stability interact with these domains. The major Myc protein product, 439 amino acids long, is shown. Not drawn to scale. See text for details.
Figure 2 Structure of MYC gene and protein: functional domains and interactors. (Top) MYC locus. (Middle) MYC gene organization. (Bottom) Myc protein domains organization. A variety of proteins that regulate Myc activity and stability interact with these domains. The major Myc protein product, 439 amino acids long, is shown. Not drawn to scale. See text for details.CC BY · PubMed Central
Figure 3 Structure-function schematic of the members of the extended Myc/Max network. Known functional domains of different network members are summarized. TAD: transactivation domain; DBD: DNA binding domain; P: position of known phosphorylation sites; SID: mSin3 interaction domain; TRD: trans-repression domain; T-domain: T-box DNA binding domain; DCD: dimerization and cytoplasmic localization domain. MCR: MondoA conserved region. Not drawn to scale. See text for details.
Figure 3 Structure-function schematic of the members of the extended Myc/Max network. Known functional domains of different network members are summarized. TAD: transactivation domain; DBD: DNA binding domain; P: position of known phosphorylation sites; SID: mSin3 interaction domain; TRD: trans-repression domain; T-domain: T-box DNA binding domain; DCD: dimerization and cytoplasmic localization domain. MCR: MondoA conserved region. Not drawn to scale. See text for details.CC BY · PubMed Central
Figure 4 (Top) Multiple sequence alignment of the basic, helix-loop-helix, leucine zipper (bHLHLZ) domains of selected members of the Myc/Max/Mad network. Myc and Max monomers share ~60% similarity at the protein level in their bHLHLZ domains. Sequence conservations among Myc, Max, and Mad proteins are boxed and highlighted using the same coloring scheme as in the schematic of the bHLHLZ domain at the top. Conservation anomalies between the bHLHLZ domains of Max and Mad family relative to the three Myc paralogs [84] are indicated with a star (*) below the multiple alignment. Green dots indicate critical DNA recognition residues while red dots indicate important dimerization residues mutated in Omomyc. (Bottom) Available X-ray structures of complexes bound to the canonical E-box DNA recognition sequence: Myc-Max (PDB ID: 1NKP, 1.8 Å resolution), Mad-Max (PDB ID: 1NLW, 2 Å), Max-Max (PDB ID: 1AN2, 2.9 Å), and Omomyc (PDB ID: 15I0, 2.7 Å). Dimer assembly occurs through the helix-loop-helix (HLH) and leucine zipper (LZ) regions, while DNA binding takes place mainly through the basic (b) region and extends into the HLH region.
Figure 4 (Top) Multiple sequence alignment of the basic, helix-loop-helix, leucine zipper (bHLHLZ) domains of selected members of the Myc/Max/Mad network. Myc and Max monomers share ~60% similarity at the protein level in their bHLHLZ domains. Sequence conservations among Myc, Max, and Mad proteins are boxed and highlighted using the same coloring scheme as in the schematic of the bHLHLZ domain at the top. Conservation anomalies between the bHLHLZ domains of Max and Mad family relative to the three Myc paralogs [84] are indicated with a star (*) below the multiple alignment. Green dots indicate critical DNA recognition residues while red dots indicate important dimerization residues mutated in Omomyc. (Bottom) Available X-ray structures of complexes bound to the canonical E-box DNA recognition sequence: Myc-Max (PDB ID: 1NKP, 1.8 Å resolution), Mad-Max (PDB ID: 1NLW, 2 Å), Max-Max (PDB ID: 1AN2, 2.9 Å), and Omomyc (PDB ID: 15I0, 2.7 Å). Dimer assembly occurs through the helix-loop-helix (HLH) and leucine zipper (LZ) regions, while DNA binding takes place mainly through the basic (b) region and extends into the HLH region.CC BY · PubMed Central
Figure 5 Chemical structures of 10058-F4, 10074-A4, and 10074-G5 inhibitors of Myc-Max dimerization identified through high-throughput screening of a finite combinatorial library. See text for details.
Figure 5 Chemical structures of 10058-F4, 10074-A4, and 10074-G5 inhibitors of Myc-Max dimerization identified through high-throughput screening of a finite combinatorial library. See text for details.CC BY · PubMed Central
Figure 6 Chemical structures of JY-3-094 and 3jc48-3, improved analogs of compound 10074-G5.
Figure 6 Chemical structures of JY-3-094 and 3jc48-3, improved analogs of compound 10074-G5.CC BY · PubMed Central
Figure 7 Chemical structures of Mycro3, KJ-Pyr-9, sAJM589, and MYCMI-6 inhibitors of Myc-Max dimerization identified through high-throughput screening of diverse small-sized compound libraries.
Figure 7 Chemical structures of Mycro3, KJ-Pyr-9, sAJM589, and MYCMI-6 inhibitors of Myc-Max dimerization identified through high-throughput screening of diverse small-sized compound libraries.CC BY · PubMed Central
Figure 8 Chemical structures of MYRA-A, NSC308848, JKY-2-169, and KSI-3716 inhibitors of Myc-Max binding to DNA identified through high-throughput screening or specifically engineered to disrupt protein-DNA interactions. See text for details.
Figure 8 Chemical structures of MYRA-A, NSC308848, JKY-2-169, and KSI-3716 inhibitors of Myc-Max binding to DNA identified through high-throughput screening or specifically engineered to disrupt protein-DNA interactions. See text for details.CC BY · PubMed Central
Figure 9 Chemical structures of PKUMDL-YC-1201 to -1205 compounds that disrupt Myc-Max dimerization identified through virtual screening (VS) multi-conformational docking against a reference ensemble of Myc disordered conformations generated through molecular dynamics (MD) simulations. Details are provided in the text.
Figure 9 Chemical structures of PKUMDL-YC-1201 to -1205 compounds that disrupt Myc-Max dimerization identified through virtual screening (VS) multi-conformational docking against a reference ensemble of Myc disordered conformations generated through molecular dynamics (MD) simulations. Details are provided in the text.CC BY · PubMed Central
Figure 10 Chemical structure of 7594-0035 Myc-Max inhibitor identified in silico utilizing the Myc-Max 1NKP X-ray structure, yet targeting a previously reported disordered binding region for 10074-G5 but in ordered form. See Section 3.1.4 for further details.
Figure 10 Chemical structure of 7594-0035 Myc-Max inhibitor identified in silico utilizing the Myc-Max 1NKP X-ray structure, yet targeting a previously reported disordered binding region for 10074-G5 but in ordered form. See Section 3.1.4 for further details.CC BY · PubMed Central
Figure 11 Chemical structure of VPC-70063 identified in silico by screening of the largest purchasable chemical space of the ZINC database that targets a novel binding site located at the Myc-Max/DNA interface of the 1NKP Myc-Max X-ray structure. See Section 3.1.4 for further details.
Figure 11 Chemical structure of VPC-70063 identified in silico by screening of the largest purchasable chemical space of the ZINC database that targets a novel binding site located at the Myc-Max/DNA interface of the 1NKP Myc-Max X-ray structure. See Section 3.1.4 for further details.CC BY · PubMed Central
Figure 12 Chemical structures of representative Max-Max stabilizers that alter Myc-Max function by blocking binding to equivalent DNA binding sites. See text for details.
Figure 12 Chemical structures of representative Max-Max stabilizers that alter Myc-Max function by blocking binding to equivalent DNA binding sites. See text for details.CC BY · PubMed Central
Figure 13 Binding sites for structurally diverse Myc-Max inhibitors mapped along Myc and Max protein sequences. Residue numbering above a protein sequence follows the convention for individual monomers, while that bellow follows the numbering in the Myc-Max X-ray structure. Binding sites described in the text are numbered and illustrated by circle-enclosed digits. The coloring scheme suggests three major druggable sites on Myc, both in disordered monomeric form or in the functional ordered form of the Myc-Max heterodimer.
Figure 13 Binding sites for structurally diverse Myc-Max inhibitors mapped along Myc and Max protein sequences. Residue numbering above a protein sequence follows the convention for individual monomers, while that bellow follows the numbering in the Myc-Max X-ray structure. Binding sites described in the text are numbered and illustrated by circle-enclosed digits. The coloring scheme suggests three major druggable sites on Myc, both in disordered monomeric form or in the functional ordered form of the Myc-Max heterodimer.CC BY · PubMed Central
Figure 14 Three independent binding sites identified in silico at the Myc-Max/DNA and Myc-Max dimerization interfaces (colored meshed surfaces). The sites were identified by probing the surface with virtual atoms (colored alpha spheres within the three found pockets). The image was generated with Molecular Operating Environment (MOE). See text for details.
Figure 14 Three independent binding sites identified in silico at the Myc-Max/DNA and Myc-Max dimerization interfaces (colored meshed surfaces). The sites were identified by probing the surface with virtual atoms (colored alpha spheres within the three found pockets). The image was generated with Molecular Operating Environment (MOE). See text for details.CC BY · PubMed Central

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Metadata

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
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
  • 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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