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.
Marek Wanior  1  2 ,  Franziska Preuss  1  2 ,  Xiaomin Ni  1  2 ,  Andreas Krämer  1  2  3 ,  Sebastian Mathea  1  2 ,  Tamara Göbel  1 ,  David Heidenreich  1  2 ,  Svenja Simonyi  1 ,  Astrid S Kahnt  1 ,  Andreas C Joerger  1  2  4 ,  Stefan Knapp  1  2  4  3
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2. Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences (BMLS), Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. Frankfurt Cancer Institute (FCI), Paul-Ehrlich-Str. 42-44, 60596 Frankfurt am Main, Germany.
  • 4. German Translational Cancer Network (DKTK), Frankfurt/Mainz Site, 60438 Frankfurt am Main, Germany.
PMID: 33216538 DOI: 10.1021/acs.jmedchem.0c01242
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.

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