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

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.

• Authors: Seung H Choi, Madhupriya Mahankali, Sang Jun Lee, Mitchell Hull, H Michael Petrassi, Arnab K Chatterjee, Peter G Schultz, Katherine A Jones, Weijun Shen
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 12 Issue 11 Pg. 2715-2719 (11 17 2017) ISSN: 1554-8937 [Electronic] United States
• PMID: 28976731 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• MAX protein, human
• Proto-Oncogene Proteins c-myc
• Small Molecule Libraries

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Burkitt Lymphoma (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• HEK293 Cells
• Humans
• Protein Interaction Maps (drug effects)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, metabolism)
• Small Molecule Libraries (chemistry, pharmacology)