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  3. 2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

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

  • J Enzyme Inhib Med Chem. 2022 Dec;37(1):349-372. doi: 10.1080/14756366.2021.2015344.
Mostafa M Elbadawi 1 2,  Wagdy M Eldehna 2,  Amer Ali Abd El-Hafeez 3 4,  Warda R Somaa 5,  Amgad Albohy 6,  Sara T Al-Rashood 7,  Keli K Agama 8,  Eslam B Elkaeed 9,  Pradipta Ghosh 4 10 11 12,  Yves Pommier 8,  Manabu Abe 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Graduate School of Science, Hiroshima University, Hiroshima, Japan.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 3 Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
  • 4 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 5 Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.
  • 7 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
  • 8 Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 9 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
  • 10 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 11 Moores Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 12 Veterans Affairs Medical Center, La Jolla, CA, USA.
PMID: 34923887 DOI: 10.1080/14756366.2021.2015344
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.

Keywords

EGFR inhibitors; FAK inhibitors; Quinoline; anticancer; molecular dynamics.

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