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Design, synthesis and evaluation of novel inhibitors of class II PI4Ks and RIPK2/3 kinases
Misehe, Mbilo ; Nencka, Radim (advisor) ; Soural, Miroslav (referee) ; Baszczyňski, Ondřej (referee)
Synthetic kinase inhibitors are chemical tools to investigate cellular roles of kinase enzymes and, potentially, find new treatments for various diseases that are connected with their dysregulated expressions and activities. This thesis focuses on two projects that were devoted to design, synthesize and evaluate novel compounds as kinase inhibitors. In a first project, employing structure-based docking methods, novel 7-aryl- or 7-heteroaryl-substituted 4-aminoquinazoline-6-carboxamide compounds were developed as inhibitors of class II phosphatidylinositol 4-kinases (PI4K2A/2B). A simple synthetic approach enabled the preparation and the functionalization of the 4-aminoquinazoline scaffold in six steps. Enzymatic evaluation for activity and selectivity against PI4Ks (i.e., PI4K2A and class III PI4Ks) highlighted several compounds with low micromolar potency and good selectivity against PI4K2A. Moreover, the binding mode of the new compounds in the conserved ATP-binding sites of class II PI4Ks was corroborated by X-ray crystallography. This suggests the applied rationale of the design can be a strategical option to obtain more potent and selective PI4K class II inhibitors, to conduct additional investigations on these kinases. In a second project, novel 4,6- and 4,6,7-substituted quinazoline...
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