Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity

SMARCA2is an attractive synthetic lethality target for human cancerswith SMARCA4 deficiency. Herein, we report the design, synthesis,and biological evaluation of selective SMARCA2 protein degraders developedusing the proteolysis targeting chimera (PROTAC) technology. Our effortshave led to the discovery of a series of potent and selective SMARCA2degraders, exemplified by SMD-3040. SMD-3040 degrades SMARCA2 proteinwith a low nanomolar DC50 and D (max) > 90% and demonstrates an excellent degradation selectivity forSMARCA2 protein over SMARCA4 protein. It displays potent cell growthinhibitory activity in a panel of SMARCA4-deficient cancer cell linesand has much weaker activity in SMARCA4 wild-type cancer cell lines.SMD-3040 achieves strong tumor growth inhibition in two SMARCA4-deficientxenograft models at well-tolerated dose schedules. Further optimizationof SMD-3040 may lead to the discovery of new therapies for the treatmentof human cancers with SMARCA4 deficiency.

Automated summary

Researchers have designed and synthesized selective SMARCA2 protein degraders using PROTAC technology, leading to the discovery of potent and selective SMARCA2 degraders such as SMD-3040. SMD-3040 effectively degrades SMARCA2 protein with high selectivity over SMARCA4 protein. It demonstrates strong cell growth inhibitory activity in SMARCA4-deficient cancer cells and exhibits significant tumor growth inhibition in SMARCA4-deficient xenograft models.