PRT3789 Is a First-in-Human SMARCA2-Selective Degrader That Induces Synthetic Lethality in SMARCA4 -Mutated Cancers

SMARCA2 and SMARCA4 are the core catalytic subunits of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. Approximately 10% of patients with non-small cell lung cancer patients harbor SMARCA4 mutations, resulting in protein loss or loss-of-function alterations. These SMARCA4-deficient cancers are highly dependent on SMARCA2 for proliferation, growth, and survival, making SMARCA2 a promising synthetic lethal target. In this study, we developed and characterized PRT3789, a clinical-stage SMARCA2-selective targeted protein degrader. It induced polyubiquitination at lysine residues unique to SMARCA2 through stable ternary complex formation with the Von Hippel-Lindau E3 ligase. The selectivity was driven by interactions with an extended loop unique to SMARCA2, as revealed by structure-based analyses. PRT3789 promoted selective degradation of SMARCA2 while sparing its highly homologous paralog, SMARCA4. In SMARCA4-deficient models, SMARCA2 degradation disrupted SWI/SNF complex integrity by inducing dissociation of multiple subunits, leading to downstream transcriptional reprogramming. PRT3789 induced robust tumor growth inhibition and regression in SMARCA4-deficient models, both as monotherapy and in combination with targeted therapies or chemotherapies. In contrast, SMARCA4 wild-type models exhibited minimal response despite confirmed SMARCA2 degradation, consistent with SMARCA4 sparing and preserved SWI/SNF complex integrity. In clinical settings, PRT3789 reduced SMARCA2 protein levels in peripheral blood mononuclear cells from patients with SMARCA4-mutated cancers. Initial signs of clinical activity have been observed, including RECIST-confirmed partial responses. Together, these findings demonstrate the selective targeting of SMARCA2 and the potential for a favorable therapeutic index with PRT3789. Phase I/II clinical trials with PRT3789 are ongoing in biomarker-selected patients with SMARCA4-mutated solid tumors. SIGNIFICANCE: PRT3789 selectively degrades SMARCA2 and demonstrates activity in SMARCA4-deficient cancers while sparing wild-type models, validating paralog synthetic lethality, and supporting clinical development in SMARCA4-mutated patients, a population with high unmet need.