Computational and Synthetic approach with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S triple mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC)

• Published in: Bioorganic chemistry Vol. 107; p. 104612
• Main Authors: Karnik, Kshipra S., Sarkate, Aniket P., Tiwari, Shailee V., Azad, Rajaram, Burra, Prasad V.L.S., Wakte, Pravin S.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.02.2021; Elsevier
• Subjects: Anticancer activity; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; EGFR; Life Sciences & Biomedicine; Molecular docking; Molecular dynamics simulations; Physical Sciences; QSAR; Quinoline; Science & Technology; Suzuki coupling; NSCLC; Anticancer activity; RMSF; T790M; RMSD; Molecular dynamics simulations; Cys797 to Ser797 (C797S); ADMET; EGFR; Molecular docking; PDB; Suzuki coupling; Mol MW; NPT; QSAR; Quinoline; XP; MD simulations; WT; AMBER99; TYROSINE KINASE INHIBITORS; DESIGN; COMPLEX; DOCKING; EPIDERMAL-GROWTH-FACTOR
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104612

[Display omitted] •Novel substituted quinoline derivatives were designed and synthesized serving as new L858R/T790M/C797S triple mutant EGFR-TKIs.•Among the synthesized compounds, 5b, 5f, 5h, 5j and 5n showed potent anti-proliferation and EGFR L858R/T790M/C797S enzyme-based inhibition.•Most potent compound 5j, inhibited EGFR L858R/T790M/C797S with IC50 value of 113 nM. 5j inhibited HCC827 and H1975 cells in vitro with IC50 values of 0.0042 µM and 0.02 µM, respectively.•Compound 5j induced early and late apoptosis of 16.7% and 4.1% in comparison with control along with cell cycle arrest at G0/G1 phase. New substituted quinoline derivatives were designed and synthesized via a five-step modified Suzuki coupling reaction. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. All docking studies confirmed high potency and flexibility towards wild type as well as a mutated enzyme. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M/C797S and L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Most of the quinoline derivatives revealed a significant cytotoxic effect. The IC50 values of 4-(4-methylquinolin-2-yl)phenyl 4-(chloromethyl)benzoate (5j) were found to be 0.0042 µM, 0.02 µM, 1.91 µM, 3.82 µM and 3.67 µM while IC50 values of osimertinib were 0.0040 µM, 0.02 µM, ND, 0.99 µM and 1.22 µM, respectively. Compound 5j has shownexcellent inhibitory activities against EGFR kinases triple mutant with IC 50 value 1.91 µM. It was observed that, compared to H1975, A549 and A431 cell lines, synthesized compounds significantly inhibited proliferation of the HCC827 cell line. These data suggested that synthesized compounds showed promising selective anticancer activity against tumor cells harboring EGFR Del E746-A750. The potency of compound 5j was compared through molecular dynamic simulations andan insilicoADMET study. QSAR models were generated and the best model was correctly compared with respect to predicted and observed activity of compounds. The built model will assist to design, refine and construct novel substituted quinoline derivatives as potent EGFR inhibitors in near future.