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 w...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(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.展开更多
Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell ...Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell proliferation,migration,and invasion by regulating chromatin morphology and gene expression,and is closely related to the development of non-small cell lung cancer(NSCLC).1 However,the underlying mechanism of LSD1 on cell proliferation and migration remains unclear.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81430085 and 81773562 for Hongmin Liuand 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)+3 种基金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).
文摘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(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.
基金supported by the National Natural Science Foundation of China(No.U2004101 for Peng-xing He,No.U21A20416 for Hong-min Liu).
文摘Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell proliferation,migration,and invasion by regulating chromatin morphology and gene expression,and is closely related to the development of non-small cell lung cancer(NSCLC).1 However,the underlying mechanism of LSD1 on cell proliferation and migration remains unclear.
