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

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.

• Authors: Nicholas B Struntz, Andrew Chen, Anja Deutzmann, Robert M Wilson, Eric Stefan, Helen L Evans, Maricela A Ramirez, Tong Liang, Francisco Caballero, Mattheus H E Wildschut, Dylan V Neel, David B Freeman, Marius S Pop, Marie McConkey, Sandrine Muller, Brice H Curtin, Hanna Tseng, Kristen R Frombach, Vincent L Butty, Stuart S Levine, Clementine Feau, Sarah Elmiligy, Jiyoung A Hong, Timothy A Lewis, Amedeo Vetere, Paul A Clemons, Scott E Malstrom, Benjamin L Ebert, Charles Y Lin, Dean W Felsher, Angela N Koehler
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 26 Issue 5 Pg. 711-723.e14 (05 16 2019) ISSN: 2451-9448 [Electronic] United States
• PMID: 30880155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• KI-MS2-008
• Lactams
• MNT protein, human
• Polycyclic Compounds
• Proto-Oncogene Proteins c-myc
• Repressor Proteins
• Small Molecule Libraries

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (chemistry, genetics, metabolism)
• Cell Line
• Dimerization
• Disease Models, Animal
• Humans
• Lactams (chemical synthesis, pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasms (drug therapy)
• Polycyclic Compounds (chemical synthesis, pharmacology, therapeutic use)
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Rats
• Repressor Proteins (chemistry, genetics, metabolism)
• Small Molecule Libraries (pharmacology, therapeutic use)
• Transcription, Genetic (drug effects)
• Ultraviolet Rays