7MGK
TNNI3K complexed with 1-(3,5-dichloro-4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea
Summary for 7MGK
| Entry DOI | 10.2210/pdb7mgk/pdb |
| Descriptor | Serine/threonine-protein kinase TNNI3K, N-(3,5-dichloro-4-{[6-(methylamino)pyrimidin-4-yl]oxy}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea (3 entities in total) |
| Functional Keywords | cark, kinase, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 141442.44 |
| Authors | Shewchuk, L.M. (deposition date: 2021-04-12, release date: 2021-11-10, Last modification date: 2024-04-03) |
| Primary citation | Patterson, J.R.,Graves, A.P.,Stoy, P.,Cheung, M.,Desai, T.A.,Fries, H.,Gatto Jr., G.J.,Holt, D.A.,Shewchuk, L.,Totoritis, R.,Wang, L.,Kallander, L.S. Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity Against VEGFR2, p38 alpha , and B-Raf. J.Med.Chem., 64:15651-15670, 2021 Cited by PubMed Abstract: A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an tool compound (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as , are favorable leads for discovering novel medicines for cardiac diseases. PubMed: 34699203DOI: 10.1021/acs.jmedchem.1c00700 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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