Journal Article

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

Al-Rashood, Sara T., Elkaeed, Eslam B., Elbadawi, Mostafa M., Abd El-Hafeez, Amer Ali, Ghosh, Pradipta, Somaa, Warda R., Pommier, Yves, Agama, Keli K., Albohy, Amgad, Abe, Manabu, Eldehna, Wagdy M.

2022

Overview

In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC 50 s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC 50 s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition.

• Publisher: Taylor & Francis,Taylor & Francis Ltd,Taylor & Francis Group
• Subject: Angiogenesis / anticancer / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antitumor activity / Antitumor agents / Apoptosis - drug effects / Cancer therapies / Cell growth / Cell Proliferation - drug effects / Clinical trials / Colorectal cancer / DNA topoisomerase / Dose-Response Relationship, Drug / Drug Screening Assays, Antitumor / EGFR inhibitors / Enzymes / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - metabolism / FAK inhibitors / Focal adhesion kinase / Focal Adhesion Kinase 1 - antagonists & inhibitors / Focal Adhesion Kinase 1 - metabolism / Humans / Kinases / Medical research / Metastasis / Models, Molecular / molecular dynamics / Molecular modelling / Molecular Structure / Pharmaceuticals / Pharmacy / Protein Kinase Inhibitors - chemical synthesis / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Quinoline / Quinolines / Quinolines - chemical synthesis / Quinolines - chemistry / Quinolines - pharmacology / R&D / Research & development / Research Paper / Structure-Activity Relationship / Tumor Cells, Cultured