Abstract
Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of hybrid small molecules (5a–5g) was designed and synthesized based on chemical moieties derived from two marine natural products (Meridianin E and Leucettamine B). Over a panel of 14 cancer-related kinases, a single dose of 10 µM of the parent hybrid 5a possessing the benzo[d][1,3]dioxole moiety of Leucettamine B was able to inhibit the activity of FMS, LCK, LYN, and DAPK1 kinases with 82.5 ± 0.6, 81.4 ± 0.6, 75.2 ± 0.0, and 55 ± 1.1%, respectively. Further optimization revealed the most potent multiple kinase inhibitor of this new series (5g) with IC50 values of 110, 87.7, and 169 nM against FMS, LCK, and LYN kinases, respectively. Compared to imatinib (FDA-approved multiple kinase inhibitor), compound 5g was found to be ~ 9- and 2-fold more potent than imatinib over both FMS and LCK kinases, respectively. In silico docking simulation models of the synthesized compounds within the active site of FMS, LCK, LYN, and DAPK1 kinases offered reasonable explanations of the elicited biological activities. In an in vitro anticancer assay using a library of 60 cancer cell lines that include blood, lung, colon, CNS, skin, ovarian, renal, prostate, and breast cancers, it was found that compound 5g was able to suppress 60 and 70% of tumor growth in leukemia SR and renal RXF 393 cell lines, respectively. Moreover, an ADME study indicated a suitable profile of compound 5g concerning cell permeability and blood-brain barrier (BBB) impermeability, avoiding possible CNS side effects. Accordingly, compound 5g is reported as a potential lead towards novel antiproliferative marine-derived kinase modulators.
Highlights
The process of drug development from marine organisms is a prehistoric praxis.To date, more than 20,000 marine natural products (MNPs) have been isolated from ocean life-forms
To date, only eight anticancer drugs of marine origin were approved by the US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMEA), or the Australian Therapeutic
3 of in we report our rational design, optimization, synthetic routes, in vitro and silico biological evaluation of the newly synthesized marine-derived compounds 5a–5g
Summary
The process of drug development from marine organisms is a prehistoric praxis. To date, more than 20,000 marine natural products (MNPs) have been isolated from ocean life-forms. Over the past two decades, drug development has shifted from the random screening of large compound libraries of synthetic origin using high-throughput cell-based cytotoxicity assays to screening against clinically validated molecular targets [7,8,9] This new target-based discovery aims to enhance the efficacy and selectivity of treatment by offering new drug candidates that block disease mechanisms in a defined and specific way. With the great potential of these two MNPs (Meridianin E and Leucettamine B) to afford new more potent kinase inhibitors, further investigations in this field are highly needed This encouraged us to apply a structure-based drug design strategy towards the development of a new marine-inspired potential kinase inhibitor (5a, Figure 1).
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