Abstract
This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98), Bayesian model (ROC = 0.86) and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED) based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees) similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H)-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI50 as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series, which is based on a new kinase scaffold with interesting chemical diversification capabilities, showed that it exhibits its “emergent” properties by perturbing multiple unexplored kinase pathways.
Highlights
Within the past years, a huge number of researches on the synthesis, structure-activity relationships (SAR) and the anticancer activities of the urea derivatives were reported [1]
Bearing this fact in mind, we decided to explore this branch and tried to develop a computational protocol which can lead to the discovery of new generations of kinase inhibitors with cancericidal activity based on new heterocyclic urea derivatives
It is preferable that we find a highly selective inhibitor, but we didn’t let such restriction prevent us from choosing compounds that show selectivity against different kinases while showing anticancer activity hoping that it might be clinically safe
Summary
A huge number of researches on the synthesis, structure-activity relationships (SAR) and the anticancer activities of the urea derivatives were reported [1]. We didn’t restrict choice on those compounds that are merely selective on a specific kinase as this is practically very difficult This didn’t deter the development of clinically significant kinase inhibitors and the evidence is that most approved kinase inhibitors have limited selectivity and target kinases [4,5,6]. This is with the exception of the highly selective inhibitor lapatinib [7].Restricting choice on highly selective compounds is very difficult if we take into consideration a large part of the kinome panel due to the high similarity of the binding site among different kinases. It is preferable that we find a highly selective inhibitor, but we didn’t let such restriction prevent us from choosing compounds that show selectivity against different kinases while showing anticancer activity hoping that it might be clinically safe
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