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
  • 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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