Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human...

Selective targeting SMARCA2 by degradation represents a promising new therapeutic strategy for human cancers harboring deficient SMARCA4. Herein we report the discovery of highly potent, selective and oral available SMARCA2 PROTAC degraders, as exemplified by SMD-6346. SMD-6346 achieves DC₅₀ = 3.3 nM and D_max > 90% against SMARCA2 and only modest activity against SMARCA4 (DC₅₀ > 1000 nM, D_max = 46%). SMD-6346 potently and effectively inhibits cell growth in SMARCA4-deficient cancer cell lines and displays minimal cell growth inhibition activity in SMARCA2/4 wild-type cancer cell lines. SMD-6346 attains an excellent pharmacokinetic profile and 61% oral bioavailability in mice. Daily oral administration of SMD-6346 induces robust SMARCA2 depletion in tumor tissues in mice and significantly inhibits tumor growth in the H838 SMARCA4-deficient xenograft model in mice. SMD-6346 is a promising, orally bioavailable SMARCA2 degrader for further optimization for the development of a new therapy for SMARCA4-deficient human cancers.