Structural optimization of 4-(imidazol-5-yl)pyridine derivatives affords broad-spectrum anticancer agents with selective B-RAFV600E/p38α kinase inhibitory activity : synthesis, in vitro assays and in silico study

Ali, Eslam M.H. and Mersal, Karim I. and Ammar, Usama M. and Zaraei, Seyed-Omar and Abdel-Maksoud, Mohammed S. and El-Gamal, Mohammed I. and Haque, Md Mamunul and Das, Tanuza and Kim, Eunice EunKyeong and Lee, Jun-Seok and Lee, Kwan Hyi and Kim, Hee-Kwon and Oh, Chang-Hyun (2022) Structural optimization of 4-(imidazol-5-yl)pyridine derivatives affords broad-spectrum anticancer agents with selective B-RAFV600E/p38α kinase inhibitory activity : synthesis, in vitro assays and in silico study. European Journal of Pharmaceutical Sciences, 171. 106115. ISSN 0928-0987 (https://doi.org/10.1016/j.ejps.2022.106115)

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Abstract

In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAF /p38α kinase inhibitory activity. Based on a previous work, a group of structural modifications were applied affording the new potential antiproliferative agents. Towards extensive biological assessment of the target compounds, an in vitro anticancer assay was conducted over NCI 60-cancer cell lines panel representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. Compounds 7c, 7d, 8b, 9b, 9c, 10c, 10d, and 11b exhibited the highest potency among the tested compounds and demonstrated sub-micromolar or one-digit micromolar GI values against the majority of the employed cell lines. Compound 10c emerged as the most potent agent with nano-molar activity over most of the cells and incredible activity against melanoma (MDA-MB-435) cell line (GI 70 nM). It is much more potent than sorafenib, the clinically used anticancer drug, against almost all the NCI-60 cell lines. Further cell-based mechanistic assays showed that compound 10c induced cell cycle arrest and promoted apoptosis in K562, MCF-7 and HT29 cancer cell lines. In addition, compound 10c induced autophagy in the three cancer cell lines. Kinase profiling of 10c showed its inhibitory effects and selectivity towards B-RAF and p38α kinases with IC values of 1.84 and 0.726 µM, respectively. Docking of compound 10c disclosed its high affinity in the kinases pockets. Compound 10c represent a promising anticancer agent, that could be optimized in order to improve its kinase activity aiming at developing potential anticancer agents. The conformational stability of compound 10c in the active site of B-RAF and p38α kinases was studied by applying molecular dynamic simulation of the compound in the two kinases for 600 ns in comparison to the native ligands.

ORCID iDs

Ali, Eslam M.H., Mersal, Karim I., Ammar, Usama M. ORCID logoORCID: https://orcid.org/0000-0002-7218-641X, Zaraei, Seyed-Omar, Abdel-Maksoud, Mohammed S., El-Gamal, Mohammed I., Haque, Md Mamunul, Das, Tanuza, Kim, Eunice EunKyeong, Lee, Jun-Seok, Lee, Kwan Hyi, Kim, Hee-Kwon and Oh, Chang-Hyun;
CORE (COnnecting REpositories)