Discovery of SD-965 as a Potent, Selective, and Efficacious STAT3 PROTAC Degrader

Signal transducer and activator of transcription 3 (STAT3) is a promising therapeutic target for human cancers and other human diseases. Herein, we report on the design, synthesis, and evaluation of novel STAT3 PROTAC degraders using high-affinity STAT3 ligands and cereblon ligands. Our study led to the discovery of SD-965 as a potent, selective, and efficacious STAT3 degrader. A single intravenous administration of SD-965 effectively induces rapid, complete, and durable depletion of STAT3 protein in mouse native and human xenograft tumor tissues with no depletion of other STAT proteins. SD-965 is capable of achieving tumor regression even with weekly administration in human leukemia and lymphoma xenograft models in mice without any signs of toxicity. SD-965 represents a promising STAT3 degrader for extensive evaluation for the treatment of human cancers and other human diseases.