Abstract 1646: Elucidating the molecular mechanism of action of the first in human SMARCA2 selective degrader PRT3789

Abstract Mammalian SWI/SNF (BAF) complexes play an important role in controlling gene expression by remodeling chromatin. SMARCA2 (BRM) and SMARCA4 (BRG1) are the core catalytic subunits of the SWI/SNF complexes and regulate the composition of nucleosomes via their ATPase activity. Approximately 10-12% of non-small cell lung cancer (NSCLC) patients harbor SMARCA4 mutations, resulting in loss of SMARCA4 protein or loss of its function (LOF). These SMARCA4-deficient cancer cells are highly dependent on the paralog gene SMARCA2 for their growth and survival. We have identified PRT3789, a first-in-class SMARCA2 selective targeted protein degrader currently in clinical trials (NCT05639751). PRT3789 promoted the formation of ternary complexes between the bromodomain of SMARCA2 or SMARCA4 with the VHL E3 ligase. Although SMARCA2 and SMARCA4 share 87% identity in their bromodomain, the structural differences between PRT3789 induced SMARCA2-VHL and SMARCA4 -VHL ternary complexes lead to more productive ubiquitination on SMARCA2 compared to SMARCA4. Proteomics and mutagenesis studies identified specific lysine residues that were ubiquitinated on the bromodomain of SMARCA2 and SMARCA4, and a unique loop on SMARCA2 that contributed to ternary complex stabilization and ubiquitination. In summary, we describe the systematic characterization of PRT3789 mediated SMARCA2 degradation and illustrate the molecular mechanism of action for how PRT3789 achieves degradation selectivity against SMARCA4. Citation Format: Min Wang, Miles Cowart, Joy Cote, Justin Kurian, Stephanie Rodgers, Chaoyi Xu, Corey Basch, Philip Pitis, Klare Bersch, Raul Leal, Liang Lu, Michael Hulse, Andrew Moore, Alexander Grego, Joseph Rager, Tom Emm, Koichi Ito, Neha Bhagwat, Andrew Combs, Sandy Geeganage, Peggy Scherle. Elucidating the molecular mechanism of action of the first in human SMARCA2 selective degrader PRT3789 [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 1646.