Original articles
Pengxing He, Shenghui Niu, Shuai Wang, Xiaojing Shi, Siqi Feng, Linna Du, Xuyang Zhang, Zhilu Ma, Bin Yu, Hongmin Liu. Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1193-1203

Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor
Pengxing Hea, Shenghui Niua, Shuai Wanga, Xiaojing Shia, Siqi Fenga, Linna Dua, Xuyang Zhanga, Zhilu Maa, Bin Yua,b, Hongmin Liua
a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China;
b State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China
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.
Key words:    WS-157    Tyrosine kinase    EGFR inhibitor    Antitumor activity   
Received: 2019-04-07     Revised: 2019-06-19
DOI: 10.1016/j.apsb.2019.06.010
Funds: This work was supported by the National Natural Science Foundation of China (Nos. 81430085 and 81773562 for Hongmin Liu and No. 81703326 for Bin Yu), the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (No. KF-GN-201902 for Bin Yu, China), Natural Science Foundation of He'nan Province of China (No. 162300410303 for Pengxin He, China), Scientific Program of Henan Province (No. 182102310123 for Bin Yu, China), China Postdoctoral Science Foundation (No. 2015M572123 for Pengxing He and Nos. 2018M630840 and 2019T120641 for Bin Yu), Key Research Program of Higher Education of Henan Province (No. 18B350009 for Bin Yu, China).
Corresponding author: Bin Yu, Hongmin Liu     Email:yubin@zzu.edu.cn;liuhm@zzu.edu.cn
Author description:
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Pengxing He
Shenghui Niu
Shuai Wang
Xiaojing Shi
Siqi Feng
Linna Du
Xuyang Zhang
Zhilu Ma
Bin Yu
Hongmin Liu

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