Abstract 2745: Identification of a selective and orally bioavailable BPTF PROTAC with anti-tumor activity in SWI/SNF mutant lung cancer

Abstract BPTF is a bromodomain and PHD finger domain-containing protein that serves as a scaffolding subunit of the ISWI family member NURF chromatin remodeling complex. Together with interchangeable catalytic subunits SMARCA1 and SMARCA5 and additional subunits RBBP4, RBBP7, the NURF complex catalyzes ATP to slide nucleosomes on DNA, exposing or occluding transcription factor binding sites, leading to transcriptional activation or repression. Dysregulation of BPTF-containing NURF complexes disrupts gene expression and contributes to oncogenesis. BPTF overexpression is observed in various cancers and correlates with poor survival. Here we report the discovery of potent and selective BPTF heterobifunctional protein degraders A123497 and A126329 utilizing BPTF bromodomain ligand NVS-BPTF-1. While BPTF bromodomain ligands are inactive across a panel of lung cancer cell lines, BPTF degraders demonstrate potent anti-tumor activity in a subset of SCLC and NSCLC models, recapitulating the genetic dependency observed in CRISPR inhibition studies. Anti-tumor activity of BPTF degraders exists in a subset of lung cancer cell line models enriched in mutations in the SMARCA2/4 catalytic subunit of SWI/SNF chromatin remodeling complex. BPTF degradation leads to loss of protein stability and chromatin binding to additional NURF complex members including catalytic subunits SMARCA1 and SMARCA5 and chromatin accessibility changes at specific genes. Unique chromatin accessibility changes observed with BPTF degraders in cell lines harboring mutant SWI/SNF suggest interplay between chromatin remodeling functions of NURF and SWI/SNF complexes. We present optimization of BPTF degraders for in vivo dosing further demonstrating the therapeutic potential for targeting BPTF-containing NURF complex in cancer. Citation Format: Wen Yan, Jay Chung, Denis E. Reyna, Dan Sherman, Sabrian Li, Sara Linker, John Lapek, Soweto Thomas, Jennifer Pizzano, Elizabeth Bortolon, Sonja Brun, Steve Kaiser, Sylvie Sakata, Ian Taylor, Jennifer Cantley, Adam Gilbert, Thomas Paul. Identification of a selective and orally bioavailable BPTF PROTAC with anti-tumor activity in SWI/SNF mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2745.