期刊
CANCER CELL
卷 36, 期 5, 页码 483-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.10.001
关键词
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资金
- National Cancer Institute [R01CA123484, RO1CA196270, P50CA180995, P30CA060553]
- New-Cures Biomedical Accelerator of Northwestern University
- H-Foundation Multi-PI Basic Science Synergy Award
- Searle Funds at the Chicago Community Trust
- Chicago Biomedical Consortium
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-moleculeMYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.
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