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

Authors

Lingying Leng, Liyue Huang, Wenbin Tu, Wei Jiang, Rohan Kalyan Rej, Srinivasa Rao Allu, Yu Wang, Mi Wang, Jelena Tošović, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang

Published in

Journal of medicinal chemistry. Jun 23, 2026. Epub Jun 23, 2026.

Abstract

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.

PMID:
42334193
Bibliographic data and abstract were imported from PubMed on 23 Jun 2026.

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