1. Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.
- Author
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Struntz 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, and Koehler AN
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Cell Line, Dimerization, Disease Models, Animal, Humans, Lactams chemical synthesis, Lactams therapeutic use, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasms drug therapy, Polycyclic Compounds chemical synthesis, Polycyclic Compounds therapeutic use, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-myc metabolism, Rats, Repressor Proteins chemistry, Repressor Proteins genetics, Small Molecule Libraries therapeutic use, Ultraviolet Rays, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Lactams pharmacology, Polycyclic Compounds pharmacology, Proto-Oncogene Proteins c-myc genetics, Repressor Proteins metabolism, Small Molecule Libraries pharmacology, Transcription, Genetic drug effects
- 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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