Design synthesis and biological evaluation of molecules targeting kinase cell signaling pathways

Abstract

ATP-competitive inhibitors have minimal selectivity for individual kinases, and newlinedeveloping such kinase inhibitors remains challenging. We designed and synthesized newlineforty-four secondary and primary amine substituted imidazo[1,2-and#945;]pyrazine newlinederivatives. Enzymatic assay and cell line studies of all the synthesized derivatives newlinewere carried out. Among synthesized derivatives only four compounds 32h, 33d, 33g newlineand 33i resulted as the most potent hits for Abl1 kinase. The IC50 value of compounds newline32h, 33d, 33i, and 33g was determined with reference drug imatinib. Only compound newline32h showed a potent IC50 value (1.15and#956;M) for Abl1 kinase. After that, compound 32h newlinewas tested on human malignant cell line K562 and non-cancerous hTERT-RPE-1 in a newlinedose-dependent manner. Compound 32h showed significant 23.7 and#956;M inhibitory newlineactivity against K562 and 41.6 and#956;M for non-cancerous hTERT-RPE-1 cell line. Further, newlinedrug-likeness properties (ADMET) of all synthesized compounds (32a-af and 33a-l) were newlinepredicted using Qikprop. After in vitro studies, the structure activity relationship of newlinesynthesized compounds was developed (Figure 5.10), and molecular docking and dynamics newlinesimulation studies validated the most potent compound 32h binding affinities and newlineconformational stability in the binding cavity. The results suggest that imidazo[1,2- newlineand#945;]pyrazine derivatives may be used as Abl1 kinase inhibitor lead scaffolds for safer and newlinemore effective anticancer drugs. newline