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

Abstract

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 (IC₅₀s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC₅₀s = 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.

Graphical Abstract

Keywords:

• Quinoline
• anticancer
• EGFR inhibitors
• FAK inhibitors
• molecular dynamics

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Correction

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (10.1080/14756366.2022.2024999).

Disclosure statement

The authors have declared no conflict of interest.

Additional information

Funding

The authors acknowledge financial support from the Researchers Supporting Project number (RSP-2021/103), King Saud University, Riyadh, Saudi Arabia. Mostafa M. Elbadawi has been supported by MEXT scholarship provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan (scholarship no. 182582). Also, Yves Pommier and Keli K. Agama have been supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, NIH (BC-006161). Moreover, Amer Ali Abd El-Hafeez was supported by an NIH-funded Cancer Therapeutics Training Program (CT2, T32 CA121938) and Pradipta Ghosh was supported by the NIH (CA238042, CA100768, and CA160911).