作者
Julien P. N. Papillon,Katsumasa Nakajima,Christopher D. Adair,Jonathan Hempel,Andriana O. Jouk,Rajeshri G. Karki,Simon Mathieu,Henrik Möbitz,Rukundo Ntaganda,Troy Smith,Michaël Visser,Susan E. Hill,Felipe K. Hurtado,Gregg Chenail,Hyo-eun C. Bhang,Anka Bric,Kay X. Xiang,Geoffrey Bushold,Tamara J. Gilbert,Anthony Vattay,Julie Dooley,Emily Costa,Isabel Park,Ailing Li,David Farley,Eugen Lounkine,Qingxia Yue,Xin Xie,Xiaoping Zhu,Raviraj Kulathila,Daniel King,Tiancen Hu,Katarina Vulic,John Cantwell,Catherine A. Luu,Zainab Jagani
摘要
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.