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 SMARCA4 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 SMARCA2 to be synthetic lethal to SMARCA4, 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 SMARCA4 mutant xenografts. Finally, we
show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib
to inhibit the growth of SMARCA4 and KRAS
G12C 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 SMARCA4 mutant cancers.