A123497

A123497 is a selective, orally bioavailable heterobifunctional protein degrader (PROTAC) targeting the Bromodomain and PHD finger-containing protein (BPTF). Developed through a collaboration between Pfizer and Arvinas, A123497 utilizes the BPTF bromodomain ligand NVS-BPTF-1 to recruit an E3 ubiquitin ligase for the targeted degradation of BPTF. BPTF is a critical scaffolding subunit of the NURF (Nucleosome Remodeling Factor) chromatin remodeling complex. Degradation of BPTF disrupts the stability and chromatin binding of the NURF complex, including its catalytic subunits SMARCA1 and SMARCA5. This agent has demonstrated potent anti-tumor activity in preclinical models of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), particularly those harboring mutations in the SMARCA2/4 subunits of the SWI/SNF complex, suggesting a synthetic lethal relationship or functional interplay between the NURF and SWI/SNF remodeling complexes.