| Literature DB >> 31679823 |
Huiying Han1, Atul D Jain2, Mihai I Truica1, Javier Izquierdo-Ferrer2, Jonathan F Anker1, Barbara Lysy1, Vinay Sagar1, Yi Luan1, Zachary R Chalmers1, Kenji Unno1, Hanlin Mok1, Rajita Vatapalli1, Young A Yoo1, Yara Rodriguez1, Irawati Kandela3, J Brandon Parker4, Debabrata Chakravarti5, Rama K Mishra6, Gary E Schiltz7, Sarki A Abdulkadir8.
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.Entities:
Keywords: MYC; MYC degradation; MYC-threonine 58 phosphorylation; PD-L1; anti-PD1; cancer therapy; immunotherapy; in silico screen; small molecules; target engagement
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Year: 2019 PMID： 31679823 PMCID： PMC6939458 DOI： 10.1016/j.ccell.2019.10.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743