9vfo | pdb_00009vfo

Crystal Structure of the NUAK1-MARK3 kinase domain chimera bound with small molecule inhibitor 2-amino-N-(5-((5-chloro-4-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide

spinqualitylabelsall models 9vfo, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9vfo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.500106Å Ligands: A1ER0 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MARK3_HUMAN Involved in the specific phosphorylation of microtubule-associated proteins for tau, MAP2 and MAP4. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Publication Abstract from PubMed NUAK1, an AMPK-related kinase overexpressed in cancers, plays a crucial role in tumor metastasis and cell survival, making it an attractive cancer therapeutic target. Herein, we report potent, selective NUAK1 inhibitors via structure-guided repurposing of a covalent JAK3 inhibitor. By capitalizing on the critical structural difference horizontal line Cys909 in JAK3 versus Glu139 in NUAK1 horizontal line we substituted the electrophilic warhead with glutamate-favoring moieties, a modification that confers selective NUAK1 targeting. Supporting this design rationale, cocrystal structures verify the specific engagement of these moieties with the Glu139 residue of NUAK1. Among the synthesized analogs, candidate compound 10i exhibits subnanomolar NUAK1 inhibition (IC(50) = 0.49 nM) and kinome-wide selectivity. Besides, 10i suppresses proliferation, migration, and invasion of triple-negative breast cancer cells, reverses EMT markers, and shows robust antitumor efficacy in mouse xenografts. This study provides a promising lead and validates Glu139 as an anchor for selective NUAK1 targeting. Structure-Based Design of Potent and Highly Selective NUAK1 Inhibitors by Exploiting a Unique Glutamate Switch for the Prevention of Tumor Growth, Migration, and Invasion.,Li S, Wang Y, Liu X, Zhang H, Lei C, Wang Z, Zhang Y, Du X, Xu L, Li Z, Shi Y, Ning X, Cao J, Zhang ZM, Ma D, Ding K J Med Chem. 2026 Apr 9;69(7):7817-7838. doi: 10.1021/acs.jmedchem.5c03079. Epub , 2026 Mar 19. PMID:41855469 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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