Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader
STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with <i>K</i><sub>i</sub> = 3.5 μM binding affinity, we obtained AK-068 with <i>K</i><sub>i</sub> = 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 DC<sub>50</sub> 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.
Authors
- Renqi Xu
- Chao‐Yie Yang (ORCID: https://orcid.org/0000-0002-5445-0109)
- Jeanne A. Stuckey (ORCID: https://orcid.org/0000-0002-4192-8900)
- Yiqing Yang (ORCID: https://orcid.org/0000-0002-6522-6209)
- Jennifer L. Meagher (ORCID: https://orcid.org/0000-0003-1250-4575)
- Atsunori Kaneshige (ORCID: https://orcid.org/0000-0001-5956-3009)
- Krishnapriya Chinnaswamy
- Jelena Tošović (ORCID: https://orcid.org/0000-0001-5531-7193)
- Hoda Metwally
- Longchuan Bai (ORCID: https://orcid.org/0000-0003-1025-2925)
- Donna McEachern (ORCID: https://orcid.org/0000-0001-8662-3425)
- Leena Mallik (ORCID: https://orcid.org/0000-0002-5979-7494)
- Paul D. Kirchhoff (ORCID: https://orcid.org/0000-0002-0309-2612)
- Shaomeng Wang (ORCID: https://orcid.org/0000-0002-8782-6950)
- Mi Wang (ORCID: https://orcid.org/0000-0003-2799-5987)
- Yu Wang (ORCID: https://orcid.org/0000-0002-8833-9564)
Institutions
- University of Michigan (US)
- Medicina (PL)
- U-M Rogel Cancer Center (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01009
- Citations
- 18
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- National Cancer Institute