PRT3789 is a First-in-Human SMARCA2-Selective Degrader that Induces Synthetic Lethality in SMARCA4-Mutated Cancers

Abstract SMARCA2 and SMARCA4 are the core catalytic subunits of the SWI/SNF chromatin remodeling complex. Approximately 10% of non-small cell lung cancer (NSCLC) patients harbor SMARCA4 mutations, resulting in protein loss or loss-of-function (LOF) alterations. These SMARCA4-deficient cancers are highly dependent on SMARCA2 for proliferation, growth, and survival, making SMARCA2 a promising synthetic lethal target. Here, we developed and characterized PRT3789, a clinical-stage SMARCA2-selective targeted protein degrader (TPD). It induced polyubiquitination at lysine residues unique to SMARCA2 through stable ternary complex formation with the VHL 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 (PBMCs) 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.