Abstract
Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.
Keywords:
MYC; MYC degradation; MYC-threonine 58 phosphorylation; PD-L1; anti-PD1; cancer therapy; immunotherapy; in silico screen; small molecules; target engagement.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Immunological / pharmacology
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Antineoplastic Agents, Immunological / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / metabolism
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B7-H1 Antigen / pharmacology*
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B7-H1 Antigen / therapeutic use
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Cell Line, Tumor
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Drug Discovery / methods*
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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Feasibility Studies
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Female
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Humans
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Male
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Mice
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Neoplasms / drug therapy*
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Neoplasms / immunology
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Neoplasms / pathology
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Phosphorylation / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
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Proto-Oncogene Proteins c-myc / metabolism
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Threonine / metabolism
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Immunological
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B7-H1 Antigen
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CD274 protein, human
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MYC protein, human
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Proto-Oncogene Proteins c-myc
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Threonine
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Proteasome Endopeptidase Complex