Targeted Disruption of Myc-Max Oncoprotein Complex by a Small Molecule

  • ACS Chem Biol. 2017 Nov 17;12(11):2715-2719. doi: 10.1021/acschembio.7b00799.
Seung H Choi  1 ,  Madhupriya Mahankali  2 ,  Sang Jun Lee  2 ,  Mitchell Hull  2 ,  H Michael Petrassi  2 ,  Arnab K Chatterjee  2 ,  Peter G Schultz  2  3 ,  Katherine A Jones  1 ,  Weijun Shen  2
Affiliations
  • 1. Regulatory Biology Laboratory, The Salk Institute for Biological Studies , La Jolla, California 92037, United States.
  • 2. California Institute for Biomedical Research , La Jolla, California 92037, United States.
  • 3. Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Rd., La Jolla, California 92037, United States.
PMID: 28976731 DOI: 10.1021/acschembio.7b00799
Abstract

Myc plays important roles in cell cycle progression, cell growth, and stem cell self-renewal. Although dysregulation of Myc expression is a hallmark of human cancers, there is no Myc targeted therapy yet. Here, we report sAJM589, a novel small molecule Myc inhibitor, identified from a PCA-based high-throughput screen. sAJM589 potently disrupts the Myc-Max heterodimer in a dose dependent manner with an IC50 of 1.8 ± 0.03 μM. sAJM589 preferentially inhibits transcription of Myc target genes in a Burkitt lymphoma cell model, P493-6. Genome-wide transcriptome analysis showed that sAJM589 treatment and Myc depletion induced similar gene expression profiles. Consistently, sAJM589 suppressed cellular proliferation in diverse Myc-dependent Cancer cell lines and anchorage independent growth of Raji cells. Disruption of the Myc-Max interaction by sAJM589 reduced Myc protein levels, possibly by promoting ubiquitination and degradation of Myc. Collectively, these results suggest that sAJM589 may be a basis for the development of potential inhibitors of Myc-dependent cell growth.

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