Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration.

Authors

Ranjan Kumar Acharyya, Longchuan Bai, Haibin Zhou, Dimin Wu, Mi Wang, Hoda Metwally, Donna McEachern, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang

Published in

Journal of medicinal chemistry. Jul 05, 2026. Epub Jul 05, 2026.

Abstract

STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC₅₀ = 4 nM and D_max of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC₅₀ = 5-11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression in vivo and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.

PMID:
42402082
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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