Summary for 9BIG
| Entry DOI | 10.2210/pdb9big/pdb |
| Descriptor | Signal transducer and activator of transcription 6, [(2-{[(2S)-1-{(2S,4S)-4-[(7-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}hept-6-yn-1-yl)oxy]-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-1-benzothiophen-5-yl)di(fluoro)methyl]phosphonic acid (3 entities in total) |
| Functional Keywords | inhibitor complex, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 62241.41 |
| Authors | |
| Primary citation | Kaneshige, A.,Yang, Y.,Bai, L.,Wang, M.,Xu, R.,Mallik, L.,Chinnaswamy, K.,Metwally, H.,Wang, Y.,McEachern, D.,Tosovic, J.,Yang, C.Y.,Kirchhoff, P.D.,Meagher, J.L.,Stuckey, J.A.,Wang, S. Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader. J.Med.Chem., 2024 Cited by PubMed Abstract: STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with = 3.5 μM binding affinity, we obtained AK-068 with = 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 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. PubMed: 39311434DOI: 10.1021/acs.jmedchem.4c01009 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.304 Å) |
Structure validation
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