article · Journal of Enzyme Inhibition and Medicinal Chemistry
Researchers have developed new sets of 2-arylquinolines and 2,6-diarylquinolines aimed at improving anticancer performance. Although designed around structural activity relationships previously tied to topoisomerase I inhibition, the resulting target compounds showed weak inhibition of this enzyme, likely due to their non-coplanar structure. However, they demonstrated potent antiproliferative effects against colorectal cancer cell lines, specifically DLD-1 and HCT-116. Subsequent screening against a kinase panel revealed that these compounds act as dual inhibitors of epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK). Several specific quinolines, designated 6f, 6h, 6i, and 20f, showed potent nanomolar inhibition against EGFR, whilst compounds 6f, 6h, 6i, 16d, and 20f exhibited strong inhibition of FAK. Molecular modelling supported these dual-kinase inhibitory profiles, marking these molecules as the first reported quinolines with potent dual EGFR and FAK inhibition.
Colorectal cancer remains a significant therapeutic challenge, and therapies targeting multiple cancer pathways simultaneously can help overcome treatment resistance. Discovering chemical scaffolds capable of inhibiting both EGFR and FAK kinases provides a new molecular basis for designing targeted cancer therapies that suppress tumour cell proliferation through distinct enzymatic mechanisms.
This research is at an early discovery stage, presenting newly synthesised lead compounds tested in laboratory enzyme and cell assays. Pharmaceutical companies and oncology drug developers could use these dual EGFR and FAK inhibitors as starting points for medicinal chemistry optimisation. Considerable preclinical development, including toxicity evaluation and animal model validation, is required before any potential clinical application can be considered.
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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 <b>6f</b>, <b>6h</b>, <b>6i</b>, and <b>20f</b> were the most potent EGFR inhibitors (IC<sub>50</sub>s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines <b>6f, 6h</b>, <b>6i</b>, <b>16d</b>, and <b>20f</b> exerted the best FAK inhibition (IC<sub>50</sub>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.
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DOI: 10.1080/14756366.2021.2015344
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