4YFF

TNNI3K complexed with inhibitor 2

Summary for 4YFF

• Entry DOI: 10.2210/pdb4yff/pdb
• Related: 4YFI
• Descriptor: Serine/threonine-protein kinase TNNI3K, 3-[(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methyl-4-(morpholin-4-yl)benzenesulfonamide (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: 141422.81

Authors

Shewchuk, L.M.,Wang, L.,Lawhorn, B.G. (deposition date: 2015-02-25, release date: 2015-09-23, Last modification date: 2024-02-28)

Primary citation

Lawhorn, B.G.,Philp, J.,Zhao, Y.,Louer, C.,Hammond, M.,Cheung, M.,Fries, H.,Graves, A.P.,Shewchuk, L.,Wang, L.,Cottom, J.E.,Qi, H.,Zhao, H.,Totoritis, R.,Zhang, G.,Schwartz, B.,Li, H.,Sweitzer, S.,Holt, D.A.,Gatto, G.J.,Kallander, L.S.
Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).
J.Med.Chem., 58:7431-7448, 2015

PubMed Abstract: A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.

PubMed: 26355916
DOI: 10.1021/acs.jmedchem.5b00931

Experimental method

X-RAY DIFFRACTION (3.07 Å)