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
  • 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. [email protected].
  • 8. Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, MI, USA. [email protected].
  • 9. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 10. Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • # 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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