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  2. 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: shaomeng@umich.edu.
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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