Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors

  • Eur J Med Chem. 2015 Sep 18:102:445-63. doi: 10.1016/j.ejmech.2015.08.026.
Long Zhang  1 ,  Yingying Yang  1 ,  Haojie Zhou  1 ,  Qingmei Zheng  1 ,  Yuhao Li  1 ,  Shansong Zheng  1 ,  Shuyong Zhao  1 ,  Dong Chen  1 ,  Chuanwen Fan  2
Affiliations
  • 1. Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
  • 2. Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China. Electronic address: [email protected].
PMID: 26310890 DOI: 10.1016/j.ejmech.2015.08.026
Abstract

We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.

Keywords
A-431; EGFR-T790M; H1975; HCC827; Quinazoline derivatives.