7MGJ

TNNI3K complexed with N-methyl-4-(4-(3-(3-(trifluoromethyl) phenyl) ureido) phenoxy)picolinamide

Summary for 7MGJ

• Entry DOI: 10.2210/pdb7mgj/pdb
• Descriptor: Serine/threonine-protein kinase TNNI3K, N-methyl-4-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: kinase, cark, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 150376.93

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

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: 34699203
DOI: 10.1021/acs.jmedchem.1c00700

Experimental method

X-RAY DIFFRACTION (2.95 Å)