9big
From Proteopedia
Stat6 bound to degrader AK-1690
Structural highlights
FunctionSTAT6_HUMAN Carries out a dual function: signal transduction and activation of transcription. Involved in interleukin-4 signalling. Publication Abstract from PubMedSTAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with K(i) = 3.5 muM 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 DC(50) values of as low as 1 nM while showing minimal effect on other STAT members up to 10 muM. 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. Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader.,Kaneshige A, Yang Y, Bai L, Wang M, Xu R, Mallik L, Chinnaswamy K, Metwally H, Wang Y, McEachern D, Tosovic J, Yang CY, Kirchhoff PD, Meagher JL, Stuckey JA, Wang S J Med Chem. 2024 Sep 23. doi: 10.1021/acs.jmedchem.4c01009. PMID:39311434[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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