2. Academic Validation
  3. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

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

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: sarki.abdulkadir@northwestern.edu.
PMID: 31679823 DOI: 10.1016/j.ccell.2019.10.001
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-129600
    99.85%, c-Myc Inhibitor