Cell Chemical Biology
Volume 26, Issue 5, 16 May 2019, Pages 711-723.e14
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Article
Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription

https://doi.org/10.1016/j.chembiol.2019.02.009Get rights and content
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Highlights

  • KI-MS2-008 is a Max-binding small molecule that attenuates Myc-driven transcription

  • The compound stabilizes the Max homodimer

  • Effects on DNA occupancy and the transcriptome resemble loss of Myc

  • Treatment with KI-MS2-008 exhibits efficacy in cellular and murine cancer models

Summary

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.

Keywords

Myc
Max
chemical probe
small molecule microarray
transcription

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These authors contributed equally

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