2. Academic Validation
  3. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo

A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo

  • Nat Chem Biol. 2023 Feb 2. doi: 10.1038/s41589-022-01248-4.
Atsunori Kaneshige # 1 2,  Longchuan Bai # 2,  Mi Wang 2,  Donna McEachern 2,  Jennifer L Meagher 3,  Renqi Xu 2,  Yu Wang 2,  Wei Jiang 2,  Hoda Metwally 2,  Paul D Kirchhoff 2,  Lijie Zhao 2,  Hui Jiang 4,  Meilin Wang 5,  Bo Wen 5,  Duxin Sun 5 6,  Jeanne A Stuckey 3 6,  Shaomeng Wang 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
  • 2 Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, MI, USA.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
  • 6 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 7 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • 8 Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • 9 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • 10 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • # Contributed equally.
PMID: 36732620 DOI: 10.1038/s41589-022-01248-4
Abstract

Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

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