A126329

A126329 is a selective and orally bioavailable proteolysis-targeting chimera (PROTAC) designed to target and induce the degradation of the Bromodomain and PHD finger-containing protein (BPTF). BPTF serves as a critical scaffolding subunit of the NURF (Nucleosome Remodeling Factor) chromatin remodeling complex, which regulates gene expression by catalyzing ATP-dependent nucleosome sliding. Developed through a collaboration between Pfizer and Arvinas, A126329 utilizes the BPTF bromodomain ligand NVS-BPTF-1 to recruit an E3 ubiquitin ligase, leading to the ubiquitination and subsequent proteasomal degradation of BPTF. This degradation disrupts the stability and chromatin binding of the NURF complex, including its catalytic subunits SMARCA1 and SMARCA5. A126329 has demonstrated potent anti-tumor activity in preclinical models of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), particularly in models harboring mutations in the SMARCA2 or SMARCA4 catalytic subunits of the SWI/SNF chromatin remodeling complex, suggesting a therapeutic potential based on the functional interplay between NURF and SWI/SNF complexes.