Jack Carter

PRT3789 and chemotherapy combination were well tolerated in mice with no drug-drug interaction

IC50 Values of PRT3789 for Anti-Proliferation in Lung Cancer PDX Tumors in 3D Ex Vivo Assay

PRT3789 enhances the efficacy of KRAS G12C inhibitors in SMARCA4-deficient cancer models

| PRT3789 75 mg/kg IV efficacy and mouse body weight data

SMARCA2 bromodomain structures in Protein Data Bank

PRT3789 single dose decreases SMARCA2 protein and KRT80 mRNA expression in NCI-H838 CDX model in mice

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.

Bromodomain subfamily VIII binders and PRT3789 HiBiT degradation potency, binary complex formation

IC50 Values of PRT3789 for Anti-Proliferation in Various Tumor Cell Lines in 2D In Vitro Assay

Mechanistic and synergy profiling of PRT3789 in combination with docetaxel