1. Academic Validation
  2. 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.
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.

Figures
Products