2. Academic Validation
  3. Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

  • J Med Chem. 2019 Dec 26;62(24):11280-11300. doi: 10.1021/acs.jmedchem.9b01530.
Haibin Zhou,  Longchuan Bai,  Renqi Xu,  Yujun Zhao,  Jianyong Chen,  Donna McEachern,  Krishnapriya Chinnaswamy,  Bo Wen,  Lipeng Dai,  Praveen Kumar,  Chao-Yie Yang,  Zhaomin Liu,  Mi Wang,  Liu Liu,  Jennifer L Meagher,  Han Yi,  Duxin Sun,  Jeanne A Stuckey,  Shaomeng Wang
PMID: 31747516 DOI: 10.1021/acs.jmedchem.9b01530
Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for Cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for Cereblon/cullin 4A E3 Ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 Degrader.

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