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.