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

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.

Citation

Marek Wanior, Franziska Preuss, Xiaomin Ni, Andreas Krämer, Sebastian Mathea, Tamara Göbel, David Heidenreich, Svenja Simonyi, Astrid S Kahnt, Andreas C Joerger, Stefan Knapp. Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis. Journal of medicinal chemistry. 2020 Dec 10;63(23):14680-14699

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PMID: 33216538

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