Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy PMID: 31679823

ADC Targets in Oncology

2026-04-10

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

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

Huiying Han ¹ , Atul D Jain ² , Mihai I Truica ¹ , Javier Izquierdo-Ferrer ² , Jonathan F Anker ¹ , Barbara Lysy ¹ , Vinay Sagar ¹ , Yi Luan ¹ , Zachary R Chalmers ¹ , Kenji Unno ¹ , Hanlin Mok ¹ , Rajita Vatapalli ¹ , Young A Yoo ¹ , Yara Rodriguez ¹ , Irawati Kandela ³ , J Brandon Parker ⁴ , Debabrata Chakravarti ⁵ , Rama K Mishra ⁶ , Gary E Schiltz ⁷ , Sarki A Abdulkadir ⁸

Affiliations

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: [email protected].

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.