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Published on: November 9, 2020
Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete
Renqi Xu1, Haibin Zhou1, Longchuan Bai1
1Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
Abstract:
STAT3 is an attractive therapeutic target for cancer and other human diseases. We have previously reported the discovery of potent, selective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91. In this study, we have designed and synthesized a novel series of STAT3 degraders using a new, high-affinity STAT3 ligand with excellent chemical stability and cereblon ligands. Our efforts led to the discovery of SD-436, a highly potent and selective STAT3 degrader. A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues. SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice. SD-436 represents a promising STAT3 degrader for advanced preclinical development as a new therapy for the treatment of human cancers and other human diseases.
