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

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 inhouse diverse compound library,which was validated to be a potent and selective EGFR-TKI.WS-157 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.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.