Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/ SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2 (SMARCA2) ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/ SMARCA4-Mutant Cancers.

08:00 EDT 19th October 2018 | BioPortfolio

Summary of "Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/ SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2 (SMARCA2) ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/ SMARCA4-Mutant Cancers."

SMARCA2 (SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2), also known as BRM (Brahma homolog) is a Snf2-family DNA-dependent ATPase. BRM, and its close homolog Brahma related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPase members of the large ATP-dependent SWI/SNF chromatin remodeling complexes involved in transcriptional regulation of gene expression. No small molecules modulating SWI/SNF chromatin remodeling activity via inhibition of its ATPase activity have been reported, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show anti-proliferative activity in a BRG1-mutant lung tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1 loss-of-function settings, and should enable probing the role of SWI/SNF function more broadly in different cancer contexts and other diseases.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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