Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription. Issue 5 (16th May 2019)

• Record Type: Journal Article
• Authors: Struntz, Nicholas B.; Chen, Andrew; Deutzmann, Anja; Wilson, Robert M.; Stefan, Eric; Evans, Helen L.; Ramirez, Maricela A.; Liang, Tong; Caballero, Francisco; Wildschut, Mattheus H.E.; Neel, Dylan V.; Freeman, David B.; Pop, Marius S.; McConkey, Marie; Muller, Sandrine; Curtin, Brice H.; Tseng, Hanna; Frombach, Kristen R.; Butty, Vincent L.; Levine, Stuart S.; Feau, Clementine; Elmiligy, Sarah; Hong, Jiyoung A.; Lewis, Timothy A.; Vetere, Amedeo; Clemons, Paul A.; Malstrom, Scott E.; Ebert, Benjamin L.; Lin, Charles Y.; Felsher, Dean W.; Koehler, Angela N.;
• Is Part Of: Cell chemical biology. Volume 26:Issue 5(2019)
• Page Start: 711
• Page End: 723.e14
• Publication Date: 2019-05-16
• Subjects: Myc -- Max -- chemical probe -- small molecule microarray -- transcription; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.02.009
• Languages: English
• ISSNs: 2451-9456

Abstract

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. Graphical Abstract: 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 withKI-MS2-008 exhibits efficacy in cellular and murine cancer models Abstract : Myc/Max-mediated transcription is deregulated in most of human cancers. Struntz et al. discovered a small molecule that stabilizes the Max homodimer and attenuates Myc-driven transcription with efficacy in cellular and murine cancer models. This discovery reinforces an alternative Myc-targeting strategy and could inform development of compounds to treat Myc-dependent cancers.