1. Academic Validation
  2. Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia

Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia

  • J Med Chem. 2023 Feb 23;66(4):2717-2743. doi: 10.1021/acs.jmedchem.2c01665.
Atsunori Kaneshige 1 2 Longchuan Bai 2 Mi Wang 2 Donna McEachern 2 Jennifer L Meagher 3 Renqi Xu 2 Paul D Kirchhoff 2 Bo Wen 4 Duxin Sun 4 5 Jeanne A Stuckey 3 5 Shaomeng Wang 1 2 6 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Life Science Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
Abstract

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules.

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