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

Atsunori Kaneshige; Yiqing Yang; Longchuan Bai; Mi Wang; Renqi Xu; Leena Mallik; Krishnapriya Chinnaswamy; Hoda Metwally; Yu Wang; Donna McEachern; Jelena Tošović; Chao-Yie Yang; Paul D Kirchhoff; Jennifer L Meagher; Jeanne A Stuckey; Shaomeng Wang

doi:10.1021/acs.jmedchem.4c01009

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

J Med Chem. 2024 Sep 23. doi: 10.1021/acs.jmedchem.4c01009. Online ahead of print.

Authors

Atsunori Kaneshige^{1

2}, Yiqing Yang², Longchuan Bai², Mi Wang², Renqi Xu², Leena Mallik³, Krishnapriya Chinnaswamy³, Hoda Metwally², Yu Wang², Donna McEachern², Jelena Tošović², Chao-Yie Yang², Paul D Kirchhoff², Jennifer L Meagher³, 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 K_i = 3.5 μM binding affinity, we obtained AK-068 with K_i = 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.