6B5J

TNNI3K complexed with a 4,6-diaminopyrimidine

Summary for 6B5J

• Entry DOI: 10.2210/pdb6b5j/pdb
• Descriptor: Serine/threonine-protein kinase TNNI3K, N-methyl-3-[(6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)amino]benzene-1-sulfonamide (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q59H18
• Total number of polymer chains: 4
• Total formula weight: 141247.10

Authors

Shewchuk, L.M.,Philp, J. (deposition date: 2017-09-29, release date: 2018-04-04, Last modification date: 2024-03-13)

Primary citation

Philp, J.,Lawhorn, B.G.,Graves, A.P.,Shewchuk, L.,Rivera, K.L.,Jolivette, L.J.,Holt, D.A.,Gatto, G.J.,Kallander, L.S.
4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors.
J. Med. Chem., 61:3076-3088, 2018

PubMed Abstract: Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.

PubMed: 29561151
DOI: 10.1021/acs.jmedchem.8b00125

Experimental method

X-RAY DIFFRACTION (2.97 Å)