Abstract 7074: PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader, enhances efficacy of standard of care agents in SMARCA4 mutant tumor models.

Abstract SMARCA2 and SMARCA4 are mutually exclusive, essential catalytic subunits of human BAF complexes, which are involved in controlling gene expression through the remodeling of chromatin structure. In a subset of solid tumors, SMARCA4 is frequently mutated, rendering cancer cells with SMARCA4 loss-of-function (LOF) mutations highly dependent on SMARCA2 for proliferation and survival. This synthetic lethal dependency offers an opportunity to develop safe and effective treatment options for patients with SMARCA4MUT tumors through the development of selective SMARCA2 degraders. Here we describe the in vitro and in vivo properties of PLX-61639, a potent, selective, and orally bioavailable SMARCA2 degrader currently in clinical development. PLX-61639 was developed utilizing a monovalent direct degrader strategy where small molecules are designed to bind the target protein and induce its degradation through the recruitment of an E3 ligase complex. PLX-61639 elicits potent and selective degradation of SMARCA2 by inducing a ternary complex with the E3 ligase DCAF16. An electrophilic moiety of PLX-61639 promotes the formation of a covalent drug-E3 ligase adduct and enables extended degradation kinetics and prolonged pharmacodynamic effects. The selective degradation profile of PLX-61639 leads to robust anti-proliferative activity in SMARCA4MUT tumor models and demonstrates the synthetic lethal dependency. In vivo, daily oral administration of PLX-61639 in SMARCA4MUT mouse xenograft models exhibits sustained target degradation and dose-dependent tumor growth inhibition and regression at well-tolerated doses. In addition to single agent activity, rational combination strategies were explored, guided by SMARCA2-dependent transcriptionally regulated gene sets and/or specific co-mutations often observed in SMARCA4MUT tumors. PLX-61639 demonstrates robust combination benefit with multiple standard of care agents utilizing different modalities, suggesting potential effective treatment options for future development. The results disclosed here highlight the development of PLX-61639, a potent and selective SMARCA2 monovalent direct degrader, and demonstrate its utility in the treatment of SMARCA4MUT solid tumors. Citation Format: Greg Parker, Geoffray Leriche, Aleksandar Jamborcic, Taylor Kampert, Linette Yang, Julia Toth, Kenneth Steadman, Jay Chung, Duc Tran, Luis Lopez, Farhana Barmare, Kyohei Hayashi, Gang Liu, Jianguo Ma, Alex Campos, Meg McCarrick, Kevin Freeman-Cook, Peggy Thompson. PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader, enhances efficacy of standard of care agents in SMARCA4 mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7074.