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Cell Chem Biol DOI:10.1016/j.chembiol.2019.02.009

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.

Publication TypeJournal Article
Year of Publication2019
AuthorsStruntz, NB, Chen, A, Deutzmann, A, Wilson, RM, Stefan, E, Evans, HL, Ramirez, MA, Liang, T, Caballero, F, Wildschut, MHE, Neel, DV, Freeman, DB, Pop, MS, McConkey, M, Muller, S, Curtin, BH, Tseng, H, Frombach, KR, Butty, VL, Levine, SS, Feau, C, Elmiligy, S, Hong, JA, Lewis, TA, Vetere, A, Clemons, PA, Malstrom, SE, Ebert, BL, Lin, CY, Felsher, DW, Koehler, AN
JournalCell Chem Biol
Date Published2019 05 16
KeywordsAnimals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Line, Dimerization, Disease Models, Animal, Humans, Lactams, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasms, Polycyclic Compounds, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-myc, Rats, Repressor Proteins, Small Molecule Libraries, Transcription, Genetic, Ultraviolet Rays

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.


Alternate JournalCell Chem Biol
PubMed ID30880155
Grant ListR01 CA160860 / CA / NCI NIH HHS / United States
U01 CA176152 / CA / NCI NIH HHS / United States
U01 CA188383 / CA / NCI NIH HHS / United States
R01 CA215452 / CA / NCI NIH HHS / United States