Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective Dual FLT3/CDK2 Kinase Inhibitor

Abstract

Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC₅₀ = 2.49 μM) and has demonstrated selectivity towards FLT3 ITD-mutated MV4-11 AML cells, with an IC₅₀ of 4.3 μM. By utilizing the scaffold of the previous hit, sixteen new compounds were synthesized and screened against NCI-60 human cancer cell lines. This leads to the discovery of a potent antiproliferative compound, namely <b>5l</b>, with an average GI₅₀ value against leukemia and colon cancer subpanels equalling 3.39 and 5.97 µM, respectively. Screening against a specific set of 10 kinases that are associated with carcinogenesis indicates that compound <b>5l</b> has a potent FLT3 inhibition (IC₅₀ = 36.21 ± 1.07 nM). Remarkably, compound <b>5l</b> was three times more effective as a CDK2 inhibitor (IC₅₀ = 8.17 ± 0.32 nM) compared to sunitinib (IC₅₀ = 27.90 ± 1.80 nM). Compound <b>5l</b> was further analyzed by means of docking and molecular dynamics simulation for CDK2 and FLT3 active sites which provided a rational for the observed strong inhibition of kinases. These results suggest a novel structural scaffold candidate that simultaneously inhibits CDK2 and FLT3 and gives encouragement for further development as a potential therapeutic for leukemia and colon cancer.