2. Academic Validation
  3. Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader

Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader

  • J Med Chem. 2024 Sep 23. doi: 10.1021/acs.jmedchem.4c01009.
Atsunori Kaneshige 1 2,  Yiqing Yang 2,  Longchuan Bai 2,  Mi Wang 2,  Renqi Xu 2,  Leena Mallik 3,  Krishnapriya Chinnaswamy 3,  Hoda Metwally 2,  Yu Wang 2,  Donna McEachern 2,  Jelena Tošović 2,  Chao-Yie Yang 2,  Paul D Kirchhoff 2,  Jennifer L Meagher 3,  Jeanne A Stuckey 3 4,  Shaomeng Wang 1 2 5 4
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 Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39311434 DOI: 10.1021/acs.jmedchem.4c01009
Abstract

STAT6 is an attractive therapeutic target for human cancers and Other human diseases. Starting from a STAT6 ligand with Ki = 3.5 μM binding affinity, we obtained AK-068 with Ki = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and Cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50 values of as low as 1 nM while showing minimal effect on Other STAT members up to 10 μM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

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