SMARCA2 and SMARCA4 (also known as BRM and BRG1, respectively) are involved in the regulation of gene expression through chromatin remodeling. SMARCA4 has been shown to be mutated in multiple cancers, including 10-12% of non-small cell lung cancer (NSCLC). Because the activity of either SMARCA2 or SMARCA4 is required for chromatin remodeling to occur, SMARCA4-deficient cancer cells become highly dependent on SMARCA2 for their survival. Targeting SMARCA2 in SMARCA4-deficient cancers is believed to produce a strong synthetic lethality, resulting in SMARCA4-mutant tumor cell death while sparing normal cells that express SMARCA4 protein. However, structural similarities between the two have historically posed challenges for selective SMARCA2 inhibition.
Prelude is developing a novel series of highly potent and selective SMARCA2 protein degraders designed to specifically inhibit SMARCA4-deficient human NSCLC cell lines and primary patient derived samples. Optimization of the company’s lead compound, PRT-SCA2, is currently ongoing.