Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

Papillon, Julien and Nakajima, Katsumasa and Hempel, Jonathan and Karki, Rajeshri and Moebitz, Henrik and Ntaganda, Rukundo and Smith, Troy and Visser, Michael and Hill, Sue and Kellermann Hurtado, Felipe and Chenail, Gregg and Bhang, Hyo-Eun and Xiang, Xiaoqin and Bushold, Geoffrey and Gilbert, Tamara and Vattay, Anthony and Dooley, Julie and Costa, Emily and Adair, Chris and Jouk, Andriana and Li, Jingzhou and Bric, Anka and Park, Isabel and Li, Ailing and Farley, David and Lounkine, Eugen and Yue, Qing and Xie, Xiaoling and Kulathila, Raviraj and King, Daniel and Hu, Tiancen and Vulic, Katarina and Cantwell, John and Luu, Catherine and Jagani, Zainab (2018) Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers. Journal of Medicinal Chemistry, 61 (22). pp. 10155-10172. ISSN 15204804


SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, 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 antiproliferative 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 functions more broadly in different cancer contexts and those of other diseases.

Item Type: Article
Date Deposited: 25 Dec 2018 00:45
Last Modified: 25 Dec 2018 00:45


Email Alerts

Register with OAK to receive email alerts for saved searches.