scholarly journals New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I–Interacting Kinase (TNNi3K)

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1697 ◽  
Author(s):  
Christopher R. M. Asquith ◽  
Tuomo Laitinen ◽  
Carrow I. Wells ◽  
Graham J. Tizzard ◽  
William J. Zuercher
Keyword(s):  
Small Molecule ◽  
Cardiac Troponin ◽  
Kinase Activity ◽  
Troponin I ◽  
Negative Control ◽  
Cardiac Troponin I ◽  
Binding Motif ◽  
Binding Region ◽  
Methyl Group ◽  
Structure Activity

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I–interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure–activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition.

Abstract 177: Overexpression of Cardiac Troponin I-Interacting Kinase, a Cardiac-Specific MAPKKK, Promotes Cardiac Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Hao Tang ◽  
Kunhong Xiao ◽  
Lan Mao ◽  
Howard A Rockman ◽  
Douglas A Marchuk
Keyword(s):  
Disease Progression ◽  
Cardiac Dysfunction ◽  
Cardiac Troponin ◽  
Kinase Activity ◽  
Troponin I ◽  
Left Ventricular ◽  
Cardiac Troponin I ◽  
Cardiac Response ◽  
Kinase Assay ◽  
Idiopathic Dilated Cardiomyopathy

Cardiac Troponin I-interacting kinase (TNNI3K) is a cardiac specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicating an important role in modulating disease progression. To further investigate TNNI3K kinase activity in vivo, we have generated transgenic mice expressing both wild-type and kinase-dead versions of the human TNNI3K protein. Importantly, we show that the increased TNNI3K kinase activity induces mouse cardiac hypertrophy, and the kinase activity is required to accelerate disease progression in a left-ventricular pressure overload model of mouse cardiomyopathy. We demonstrate the clinical relevance of these observations by identifying two potential missense mutations near the kinase activation loop of TNNI3K in idiopathic dilated cardiomyopathy (DCM) human patients. Using an in vitro kinase assay and proteomics analysis, we show that TNNI3K is a dual-function kinase with Tyr and Ser/Thr kinase activity. Using antisera to TNNI3K, we show that TNNI3K protein is located at the sarcomere Z disc. These combined data suggest that TNNI3K mediates cell signaling to modulate cardiac response to stress. The essential role of the kinase activity makes TNNI3K a strong potential pharmaceutical target of kinase inhibitors for heart disease.

Sequential phosphorylation of adjacent serine residues on the N-terminal region of cardiac troponin-I: structure-activity implications of ordered phosphorylation

FEBS Letters ◽  
1995 ◽  
Vol 370 (3) ◽  
pp. 175-178 ◽  
Author(s):  
Philip G. Quirk ◽  
Valerie B. Patchell ◽  
Yuan Gao ◽  
Barry A. Levine ◽  
S. Victor Perry
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
Terminal Region ◽  
Structure Activity
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