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

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• SMARCA4 mutations occur in ~10% of non-small cell lung cancers, leading to dependency on SMARCA2.
• SMARCA2 is a synthetic lethal target in SMARCA4-deficient cancers.
• SWI/SNF chromatin remodeling complex dysfunction drives cancer progression.

Purpose of the Study:

• To develop and characterize PRT3789, a SMARCA2-selective targeted protein degrader.
• To evaluate the efficacy of PRT3789 in preclinical models of SMARCA4-deficient cancers.
• To assess the clinical activity of PRT3789 in patients with SMARCA4-mutated cancers.

Main Methods:

• Structure-based design of PRT3789 for selective SMARCA2 degradation.
• In vitro and in vivo studies in SMARCA4-deficient and wild-type cancer models.
• Pharmacodynamic assessment of SMARCA2 degradation in patient samples.
• Phase I/II clinical trials in biomarker-selected patients.

Main Results:

• PRT3789 selectively induced polyubiquitination and degradation of SMARCA2 via VHL E3 ligase.
• SMARCA2 degradation disrupted SWI/SNF complex integrity and transcriptional reprogramming in SMARCA4-deficient models.
• PRT3789 demonstrated robust tumor growth inhibition and regression in preclinical models.
• Clinical trials showed SMARCA2 protein reduction and signs of activity, including partial responses.

Conclusions:

• PRT3789 is a first-in-class SMARCA2-selective targeted protein degrader.
• PRT3789 exhibits potent anti-tumor activity in SMARCA4-deficient cancers.
• Clinical development of PRT3789 is supported by preclinical and early clinical data for patients with SMARCA4-mutated solid tumors.