Abstract 1653: Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader

Abstract SMARCA2 and SMARCA4 are essential, yet redundant, 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 commonly mutated, rendering SMARCA4-deficient cancer cells highly dependent on SMARCA2 for viability. Therefore, selectively targeting SMARCA2 in patients with SMARCA4-deficient tumors may provide an effective and safe treatment option. Targeted protein degradation (TPD) using the endogenous Ubiquitin Proteasome System (UPS) is a drug discovery strategy that may be well suited for exploiting this SMARCA2/4 synthetic lethal relationship. Here we describe the discovery and characterization of PLX-61639, a potent, selective, and orally bioavailable SMARCA2 degrader. To enable degrader discovery, we utilized 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. Rational design of compound libraries from known family VIII bromodomain binders resulted in the identification of monovalent direct degraders of SMARCA2/4. Subsequent chemical series optimization dramatically improved degradation selectivity and ultimately resulted in our development candidate, PLX-61639. PLX-61639 induces potent and selective degradation of SMARCA2 across a panel of tumor cell lines, eliciting anti-proliferative activities supportive of the synthetic lethal dependency in SMARCA4MUT tumors. A UPS focused CRISPR screen identified a specific E3 ligase complex involved in the degradation mechanism, which follow up mechanistic studies confirmed. Omics studies identified PLX-61639-induced changes to chromatin mapping and SMARCA2-dependent transcriptionally regulated gene sets. In vivo, oral administration of PLX-61639 in SMARCA4MUT xenograft models exhibited sustained target degradation and dose-dependent tumor growth inhibition at well tolerated doses. PLX-61639 had no impact on tumor growth using a SMARCA4WT xenograft model, supporting the dependency of SMARCA4 mutational status for SMARCA2-selective degrader efficacy. These results highlight the efficient discovery and development of potent and selective SMARCA2 monovalent direct degraders. Further, the preclinical characterization of our development candidate, PLX-61639, demonstrates its activity and potential utility in the treatment of SMARCA4MUT solid tumors. Citation Format: Gregory 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. Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader [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 1653.