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

Harun M Patel; Rahul Pawara; Azim Ansari; Malleshappa Noolvi; Sanjay Surana

doi:10.1016/j.bmc.2017.03.039

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

Bioorg Med Chem. 2017 May 15;25(10):2713-2723. doi: 10.1016/j.bmc.2017.03.039. Epub 2017 Mar 23.

Authors

Harun M Patel¹, Rahul Pawara², Azim Ansari², Malleshappa Noolvi³, Sanjay Surana²

Affiliations

¹ Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India. Electronic address: hpatel_38@yahoo.com.
² Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
³ Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim (Surat) 3941110, Gujarat, India.

PMID: 28366268
DOI: 10.1016/j.bmc.2017.03.039

Abstract

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-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC₅₀ value of 0.031μM 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.

Keywords: Non Small Cell Lung Cancer; Quinazoline; T790M EGFR.

MeSH terms

A549 Cells
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Binding Sites
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Proliferation / drug effects
Drug Design*
Drug Resistance, Neoplasm / drug effects
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Gefitinib
HT29 Cells
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Docking Simulation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / therapeutic use
Protein Structure, Tertiary
Quinazolines / chemical synthesis
Quinazolines / chemistry*
Quinazolines / toxicity
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolines
ErbB Receptors
Gefitinib