Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers
Year: 2024
Type: preprint
Abstract: The BRG/Brahma-associated factors (BAF or mSWI/SNF) family of chromatin remodeling complexes are critical regulators of gene expression and are major determinants of cancer and other diseases. Two paralog ATPases, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively), provide the enzymatic activity required for chromatin remodeling. Here, we discover and characterize a novel series of compounds that potently and selectively inhibit SMARCA4/SMARCA2. Mutational and biochemical studies demonstrate that these inhibitors act through a unique mode of inhibition, distinct from reported SMARCA4/SMARCA2 inhibitors. Across a range of cancer cell lines, SMARCA4/SMARCA2 inhibition resulted in lineage-specific changes in chromatin accessibility at binding sites for key transcription factors (TFs). In uveal melanoma (UM), BAF inhibition resulted in loss of enhancer occupancy of SOX10 and MITF, two essential TFs, leading to down-regulation of the melanocytic gene expression program. In a mouse xenograft model of UM, SMARCA4/SMARCA2 inhibition was well tolerated and resulted in dose-dependent tumor regression correlating with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat TF-dependent cancers.
Source: eLife
Authors: Richard C. Centore, Luis M. M. Soares, Salih Topal, Rishi G. Vaswani, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy W. Setser, David L. Lahr, Laura E. Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, GiNell Elliott, Ammar Adam, David Huang, Yunji Davenport, Shawn Schiller, Kevin J. Wilson, Johannes Voigt, Lan Xu, Martin Hentemann, David S. Millan, Ho Man Chan, Carl P. Decicco, Ryan G. Kruger, Steven F. Bellon
Institution: Foghorn Therapeutics (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4394813856