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
  • 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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