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Background and Objective <p>The cytochrome P450 (CYP) system plays a central role in drug metabolism and pharmacokinetic variability, influencing drug–drug interaction risk. The newly synthesized 4-propoxy-2-arylquinoline derivatives (MW1–3) are dual inhibitors of epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) with potent anticancer activity. This study aimed to assess their potential inhibitory effects on major human CYP enzymes to predict metabolic liabilities and interaction risks.</p> Methods <p>Inhibitory effects of MW1–3 were evaluated against CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 using pooled human liver microsomes and probe substrates quantified by validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) and high-performance liquid chromatography–ultraviolet (HPLC–UV) assays. Molecular docking was performed with the seven CYP enzymes to estimate binding affinities and identify possible enzyme–ligand interactions.</p> Results <p>All the compounds showed negligible inhibition of CYP1A2 with half-maximal inhibitory concentrations (IC<sub>50</sub>)&#xa0;&gt; 100 µM. MW1, MW2, and MW3 strongly inhibited CYP2A6 (IC<sub>50</sub> = 0.04, 0.189, and 0.118 µM, respectively) and CYP2D6 (IC<sub>50</sub> = 0.69, 1.26, and 0.69 µM, respectively), while MW3 was also a potent inhibitor of CYP2E1 (IC<sub>50</sub> = 0.12 µM). MW2 displayed moderate–strong inhibition of CYP3A4 (IC<sub>50</sub> = 1.65 µM) and CYP2C19 (IC<sub>50</sub> = 43.9 µM). Docking results complemented in vitro inhibition findings for CYP2D6 and provided structural insights into the binding modes for CYP2C9 and CYP2C19, although modeling did not account for the strong inhibition observed in smaller enzymes like CYP2A6.</p> Conclusion <p>MW1–3 exhibit selective and differential inhibition profiles toward major CYP enzymes, with CYP2A6, CYP2D6, and CYP2E1 being most affected. These findings provide essential preclinical insights for predicting potential drug–drug interactions and guiding the safe development of these arylquinoline-based anticancer agents.</p> Graphical Abstract <p></p>

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The Effect of Arylquinoline-Based EGFR and FAK Kinase Inhibitors on the Activity of Major Cytochrome P450 Enzymes

  • 期刊论文

  • 发表日期：

    2026年4月8日

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  • Fawzy Elbarbry,
  • Michael Espiritu,
  • Bethany Hecker,
  • Mostafa M. Elbadawi,
  • Wagdy M. Eldehna

摘要

Background and Objective

The cytochrome P450 (CYP) system plays a central role in drug metabolism and pharmacokinetic variability, influencing drug–drug interaction risk. The newly synthesized 4-propoxy-2-arylquinoline derivatives (MW1–3) are dual inhibitors of epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) with potent anticancer activity. This study aimed to assess their potential inhibitory effects on major human CYP enzymes to predict metabolic liabilities and interaction risks.

Methods

Inhibitory effects of MW1–3 were evaluated against CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 using pooled human liver microsomes and probe substrates quantified by validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) and high-performance liquid chromatography–ultraviolet (HPLC–UV) assays. Molecular docking was performed with the seven CYP enzymes to estimate binding affinities and identify possible enzyme–ligand interactions.

Results

All the compounds showed negligible inhibition of CYP1A2 with half-maximal inhibitory concentrations (IC50) > 100 µM. MW1, MW2, and MW3 strongly inhibited CYP2A6 (IC50 = 0.04, 0.189, and 0.118 µM, respectively) and CYP2D6 (IC50 = 0.69, 1.26, and 0.69 µM, respectively), while MW3 was also a potent inhibitor of CYP2E1 (IC50 = 0.12 µM). MW2 displayed moderate–strong inhibition of CYP3A4 (IC50 = 1.65 µM) and CYP2C19 (IC50 = 43.9 µM). Docking results complemented in vitro inhibition findings for CYP2D6 and provided structural insights into the binding modes for CYP2C9 and CYP2C19, although modeling did not account for the strong inhibition observed in smaller enzymes like CYP2A6.

Conclusion

MW1–3 exhibit selective and differential inhibition profiles toward major CYP enzymes, with CYP2A6, CYP2D6, and CYP2E1 being most affected. These findings provide essential preclinical insights for predicting potential drug–drug interactions and guiding the safe development of these arylquinoline-based anticancer agents.

Graphical Abstract