Papillon, Julien, Nakajima, Katsumasa, Hempel, Jonathan, Karki, Rajeshri, Moebitz, Henrik, Ntaganda, Rukundo, Smith, Troy, Visser, Michael, Hill, Sue, Kellermann Hurtado, Felipe, Chenail, Gregg, Bhang, Hyo-Eun, Xiang, Xiaoqin, Bushold, Geoffrey, Gilbert, Tamara, Vattay, Anthony, Dooley, Julie, Costa, Emily, Adair, Chris, Jouk, Andriana, Li, Jingzhou, Bric, Anka, Park, Isabel, Li, Ailing, Farley, David, Lounkine, Eugen, Yue, Qing, Xie, Xiaoling, Kulathila, Raviraj, King, Daniel, Hu, Tiancen, Vulic, Katarina, Cantwell, John, 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

Abstract

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
URI:	https://oak.novartis.com/id/eprint/37141