Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including <i>SMARCA4</i> in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified <i>SMARCA2</i> to be synthetic lethal to <i>SMARCA4,</i> indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in <i>SMARCA4</i> mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of <i>SMARCA4</i> and <i>KRAS G12C</i> comutant lung cancer cells. These findings provide evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against <i>SMARCA4</i> mutant cancers.