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

doi:10.1016/j.apsb.2019.06.010

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

Acta Pharm Sin B. 2019 Nov;9(6):1193-1203. doi: 10.1016/j.apsb.2019.06.010. Epub 2019 Jun 28.

Authors

Pengxing He¹, Shenghui Niu¹, Shuai Wang¹, Xiaojing Shi¹, Siqi Feng¹, Linna Du¹, Xuyang Zhang¹, Zhilu Ma¹, Bin Yu^{1

2}, Hongmin Liu¹

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.

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.

Keywords: Antitumor activity; EGFR inhibitor; Tyrosine kinase; WS-157.