2. Academic Validation
  3. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

  • Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002.
Longchuan Bai 1,  Haibin Zhou 1,  Renqi Xu 1,  Yujun Zhao 1,  Krishnapriya Chinnaswamy 2,  Donna McEachern 1,  Jianyong Chen 1,  Chao-Yie Yang 1,  Zhaomin Liu 1,  Mi Wang 1,  Liu Liu 1,  Hui Jiang 3,  Bo Wen 4,  Praveen Kumar 4,  Jennifer L Meagher 2,  Duxin Sun 4,  Jeanne A Stuckey 5,  Shaomeng Wang 6
Affiliations

Affiliations

  • 1 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
PMID: 31715132 DOI: 10.1016/j.ccell.2019.10.002
Abstract

Signal transducer and activator of transcription 3 (STAT3) is an attractive Cancer therapeutic target. Here we report 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, is a promising Cancer therapeutic strategy.

Keywords

PROTAC; SH2 domain; STAT3; c-Myc; degrader; leukemia; lymphoma; selectivity; transcriptional factor; undruggable.

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