Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle

被引：41

作者：

Patel, Harun M. ^{[1
]}

Pawara, Rahul ^{[1
]}

Ansari, Azim ^{[1
]}

Noolvi, Malleshappa ^{[2
]}

Surana, Sanjay ^{[1
]}

机构：

[1] RC Patel Inst Pharmaceut Educ & Res, Dept Pharmaceut Chem, Shirpur 425405, Maharashtra, India

[2] Shree Dhanvantary Pharm Coll, Dept Pharmaceut Chem, Surat 3941110, Gujarat, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 10期

关键词：

Quinazoline; Non Small Cell Lung Cancer; T790M EGFR; CELL LUNG-CANCER; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITORS; PAN-ERBB INHIBITOR; PHASE-II TRIAL; ACQUIRED-RESISTANCE; T790M MUTATION; IRREVERSIBLE INHIBITORS; ACCURATE DOCKING; GEFITINIB;

D O I：

10.1016/j.bmc.2017.03.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxypheny1)-1,3,4-thiadiazol-2-y1)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031 mu M against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：2713 / 2723

页数：11

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