Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription
Author(s)
Struntz, Nicholas B.
Chen, Andrew I
Deutzmann, Anja
Wilson, Robert M.
Stefan, Eric
Evans, Helen L
Ramirez, Maricela A.
Liang, Tong
Caballero, Francisco
Wildschut, Mattheus H.E.
Date Issued
May 2019
Journal
Cell Chemical Biology
Publisher
Elsevier BV
Citation
Struntz, Nicholas B. et al. "Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription." Cell Chemical Biology 26, 5 (May 2019): P711-723.e14
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.chembiol.2019.02.009
