Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

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

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)483-497.e15
JournalCancer Cell
Volume36
Issue number5
DOIs
StatePublished - Nov 11 2019

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Keywords

  • MYC
  • MYC degradation
  • MYC-threonine 58 phosphorylation
  • PD-L1
  • anti-PD1
  • cancer therapy
  • immunotherapy
  • in silico screen
  • small molecules
  • target engagement

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Han, H., Jain, A. D., Truica, M. I., Izquierdo-Ferrer, J., Anker, J. F., Lysy, B., Sagar, V., Luan, Y., Chalmers, Z. R., Unno, K., Mok, H., Vatapalli, R., Yoo, Y. A., Rodriguez, Y., Kandela, I., Parker, J. B., Chakravarti, D., Mishra, R. K., Schiltz, G. E., & Abdulkadir, S. A. (2019). Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell, 36(5), 483-497.e15. https://doi.org/10.1016/j.ccell.2019.10.001