Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis

J Med Chem. 2020 Dec 10;63(23):14680-14699. doi: 10.1021/acs.jmedchem.0c01242. Epub 2020 Nov 20.

Abstract

Accessibility of the human genome is modulated by the ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated BAF factor), which involves reading of acetylated histone tails by the bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation of chromatin remodeling leads to aberrant cell proliferation and differentiation. Here, we have characterized a set of potent and cell-active bromodomain inhibitors with pan-selectivity for canonical family VIII bromodomains. Targeted SWI/SNF bromodomain inhibition blocked the expression of key genes during adipogenesis, including the transcription factors PPARγ and C/EBPα, and impaired the differentiation of 3T3-L1 murine fibroblasts into adipocytes. Our data highlight the role of SWI/SNF bromodomains in adipogenesis and provide a framework for the development of SWI/SNF bromodomain inhibitors for indirect targeting of key transcription factors regulating cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipogenesis / drug effects*
  • Amino Acid Sequence
  • Animals
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Humans
  • Mice
  • Protein Domains / drug effects*
  • Pyridazines / chemical synthesis
  • Pyridazines / pharmacology*
  • Transcription Factors / antagonists & inhibitors*

Substances

  • DNA-Binding Proteins
  • PBRM1 protein, human
  • Pyridazines
  • SMARCA2 protein, human
  • Transcription Factors