Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFR^WT, EGFR^T790M, and EGFR^L858R).

ABSTRACT: 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 EGFR^WT, EGFR^T790M, and EGFR^L858R 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.

SUBMITTER: Abo Al-Hamd MG 

PROVIDER: S-EPMC10408569 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature