A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large cell lymphoma cell lines by inducing cell cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well tolerated dose schedules. Degradation of STAT3 protein therefore represents a promising cancer therapeutic strategy. Overall design: Global gene transcription profiling was performed in MOLM-16 and SU-DHL-1 cell lines treated with DMSO, SD36 (1000 nmol/L) or SD36Me (1000 nmol/L) for 8 and 24 hours. Independent biological replicates (such as DMSO_8h and DMSO_24h) were analyzed for each cell line under each condition. DMSO-treated samples were used as controls.