2. Academic Validation
  3. New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I-Interacting Kinase (TNNi3K)

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

  • Molecules. 2020 Apr 7;25(7):1697. doi: 10.3390/molecules25071697.
Christopher R M Asquith 1 2,  Tuomo Laitinen 3,  Carrow I Wells 2,  Graham J Tizzard 4,  William J Zuercher 2 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 4 UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
PMID: 32272798 DOI: 10.3390/molecules25071697
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.

Keywords

4-anilino-quinazolines; cardiac troponin I–interacting kinase (TNNi3K); conformational flexibility; hinge binder; kinase inhibitor design.

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