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Cancer Cell. 2019 Nov 11;36(5):483-497.e15. doi: 10.1016/j.ccell.2019.10.001. Epub 2019 Oct 31.

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy.

Author information

1
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
2
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA.
3
Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA.
4
Division of Reproductive Science in Medicine, Department of OB/GYN, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
5
Division of Reproductive Science in Medicine, Department of OB/GYN, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA.
6
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA.
7
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA.
8
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: sarki.abdulkadir@northwestern.edu.

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

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