Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2023)

Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFRWT, EGFRT790M, and EGFRL858R)

  • Mahmoud G. Abo Al-Hamd,
  • Haytham O. Tawfik,
  • Omeima Abdullah,
  • Koki Yamaguchi,
  • Masaharu Sugiura,
  • Ahmed B. M. Mehany,
  • Mervat H. El-Hamamsy,
  • Tarek F. El-Moselhy

DOI
https://doi.org/10.1080/14756366.2023.2241674
Journal volume & issue
Vol. 38, no. 1

Abstract

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Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFRWT, EGFRT790M, and EGFRL858R where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC50 = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.

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