Hybrids of Quinoline and Anilinopyrimidine: Novel EGFRT790M Inhibitors with Antiproliferative Activity against Non-Small Cell Lung Cancer Cell Lines.
Anticancer Agents Med Chem
; 20(6): 724-733, 2020.
Article
in En
| MEDLINE
| ID: mdl-32116203
ABSTRACT
BACKGROUND:
The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors.OBJECTIVE:
Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines.METHODS:
The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor.RESULTS:
Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565µM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495µM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011µM) relative to EGFRWT (IC50 = 0.913 ± 0.068µM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions.CONCLUSION:
Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Quinazolines
/
Carcinoma, Non-Small-Cell Lung
/
ErbB Receptors
/
Lung Neoplasms
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Anticancer Agents Med Chem
Journal subject:
ANTINEOPLASICOS
/
QUIMICA
Year:
2020
Type:
Article
Affiliation country:
China