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

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

doi:10.1016/j.chembiol.2019.02.009

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

Cell Chem Biol. 2019 May 16;26(5):711-723.e14. doi: 10.1016/j.chembiol.2019.02.009. Epub 2019 Mar 14.

Authors

Nicholas B Struntz¹, Andrew Chen¹, Anja Deutzmann², Robert M Wilson¹, Eric Stefan³, Helen L Evans¹, Maricela A Ramirez⁴, Tong Liang⁴, Francisco Caballero³, Mattheus H E Wildschut³, Dylan V Neel³, David B Freeman⁵, Marius S Pop⁵, Marie McConkey⁶, Sandrine Muller⁷, Brice H Curtin¹, Hanna Tseng³, Kristen R Frombach³, Vincent L Butty⁸, Stuart S Levine⁸, Clementine Feau⁷, Sarah Elmiligy⁹, Jiyoung A Hong¹⁰, Timothy A Lewis⁷, Amedeo Vetere⁷, Paul A Clemons⁷, Scott E Malstrom⁹, Benjamin L Ebert⁶, Charles Y Lin¹¹, Dean W Felsher², Angela N Koehler¹²

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
² Division of Oncology, Departments of Medicine and Pathology Stanford School of Medicine, Stanford, CA 94305, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Molecular and Human Genetics and Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Kronos Bio, Inc., Cambridge, MA 02139, USA.
⁶ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; BioMicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
¹¹ Department of Molecular and Human Genetics and Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: koehler@mit.edu.

PMID: 30880155
DOI: 10.1016/j.chembiol.2019.02.009

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.

Keywords: Max; Myc; chemical probe; small molecule microarray; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding