Discovery of\nSD-436: A Potent, Highly Selective and\nEfficacious STAT3 PROTAC Degrader Capable of Achieving Complete and\nLong-Lasting Tumor Regression

STAT3 is an attractive therapeutic target for cancer\nand other\nhuman diseases. We have previously reported the discovery of potent,\nselective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91.\nIn this study, we have designed and synthesized a novel series of\nSTAT3 degraders using a new, high-affinity STAT3 ligand with excellent\nchemical stability and cereblon ligands. Our efforts led to the discovery\nof SD-436, a highly potent and selective STAT3 degrader. A single\nintravenous administration of SD-436 at 5 mg/kg effectively induces\nrapid, complete, and durable depletion of STAT3 in mouse native and\nxenograft tumor tissues. SD-436 achieves complete and long-lasting\ntumor regression even with a weekly dosing schedule in leukemia and\nlymphoma xenograft models in mice. SD-436 represents a promising STAT3\ndegrader for advanced preclinical development as a new therapy for\nthe treatment of human cancers and other human diseases.