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

Pengxing HE; Shenghui Niu; Shuai Wang; Xiaojing Shi; Siqi Feng; Linna DU; Xuyang Zhang; Zhilu MA; Bin YU; Hongmin Liu

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

Author: Pengxing HE ¹ ; Shenghui NIU ¹ ; Shuai WANG ¹ ; Xiaojing SHI ¹ ; Siqi FENG ¹ ; Linna DU ¹ ; Xuyang ZHANG ¹ ; Zhilu MA ¹ ; Bin YU ¹ ; Hongmin LIU ¹
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1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Publication Type:Journal Article
Keywords: Antitumor activity; EGFR inhibitor; Tyrosine kinase; WS-157
From: Acta Pharmaceutica Sinica B 2019;9(6):1193-1203
CountryChina
Language:English
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 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. showed excellent inhibitory activities against EGFR (IC = 0.81 nmol/L), EGFR (IC = 1.2 nmol/L) and EGFR (IC = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. 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 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that has strong antitumor activity and , and could be used for the development of anti-lung cancer agent targeting EGFR.