Abstract
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.
Highlights
IntroductionKinases have been successfully targeted with 52 kinase inhibitors approved by the FDA to date
Kinases have been successfully targeted with 52 kinase inhibitors approved by the FDA to date.These kinase inhibitor drugs tend to be predominantly multi-targeted tyrosine kinase inhibitors for the treatment of cancer [1,2]
Despite the hinge binder being present observed in compounds 17, 16, 2 in Figures 4C–E respectively, with the dimethylamine assisting in in compound 20, the potency was significantly weaker, and this was supported by the modelling of 20 the conformational preference of the optimal inhibitor
Summary
Kinases have been successfully targeted with 52 kinase inhibitors approved by the FDA to date. TNNi3K is selectively expressed in heart tissues and has been linked to cardiac hypertrophy dilated cardiomyopathy, pressure overload-induced heart failure, and ischemia/reperfusion injury in an in-vivo neonatal rat model [5,6,7]. 2020, 25, tissues and has been linked to cardiac hypertrophy dilated cardiomyopathy, pressure overloadinduced heart failure, and ischemia/reperfusion injury in an in-vivo neonatal rat model [5,6,7]. Knockout mouse exhibited reduced ischemic injury suggesting that deletion of is cardioprotective [5,6,7] These studies suggest that TNNi3K inhibition could serve as a unique strategy. To gain additional insights into the describe a small array of new inhibitors of to gain additional insights into the structural requirements for TNNi3K inhibition.
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