Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor.

Abstract

EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of WS-157 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. WS-157 showed excellent inhibitory activities against EGFR (IC50 = 0.81 nmol/L), EGFR[d746-750] (IC50 = 1.2 nmol/L) and EGFR[L858R] (IC50 = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo, and could be used for the development of anti-lung cancer agent targeting EGFR.

• Authors: Pengxing He, Shenghui Niu, Shuai Wang, Xiaojing Shi, Siqi Feng, Linna Du, Xuyang Zhang, Zhilu Ma, Bin Yu, Hongmin Liu
• Journal: Acta pharmaceutica Sinica. B (Acta Pharm Sin B) Vol. 9 Issue 6 Pg. 1193-1203 (Nov 2019) ISSN: 2211-3835 [Print] Netherlands
• PMID: 31867165 (Publication Type: Journal Article)
• Copyright: © 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.