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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.


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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