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Title: Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. Here in this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. Ultimately, these small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [2] ;  [1] ;  [1]
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States). Dept. of Structural and Chemical Biology
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
  3. Icahn School of Medicine at Mount Sinai, New York, NY (United States). Dept. of Structural and Chemical Biology; Hostos Community College of CUNY, Bronx, NY (United States). Dept. of Natural Sciences
Publication Date:
OSTI Identifier:
1238690
Report Number(s):
BNL-111425-2015-JA
Journal ID: ISSN 1074-5521
Grant/Contract Number:
SC00112704; AC02-98CH10886; GM0080
Type:
Published Article
Journal Name:
Chemistry & Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 2; Journal ID: ISSN 1074-5521
Publisher:
Elsevier
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES