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 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 to be synthetic lethal to 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 mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of and 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 mutant cancers.