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

被引：3

作者：

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
,2
]}

Hongmin Liu ^{[1
]}

机构：

[1] School of Pharmaceutical Sciences, Zhengzhou University

[2] State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University

来源：

Acta Pharmaceutica Sinica B | 2019年 / 9卷 / 06期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

WS-157; Tyrosine kinase; EGFR inhibitor; Antitumor activity;

D O I：

暂无

中图分类号：

R730.5 [肿瘤治疗学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1193 / 1203

页数：11

共 15 条

[1] Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase1(LSD1/KDM1A)[J]. Zhonghua Li,Lina Ding,Zhongrui Li,Zhizheng Wang,Fengzhi Suo,Dandan Shen,Taoqian Zhao,Xudong Sun,Junwei Wang,Ying Liu,Liying Ma,Bing Zhao,Pengfei Geng,Bin Yu,Yichao Zheng,Hongmin Liu.Acta Pharmaceutica Sinica B. 2019(04)
[2] Br?nsted Acid‐Catalyzed Direct C( sp 2)?H Heteroarylation Enabling the Synthesis of Structurally Diverse Biaryl Derivatives[J] . Shuo Yuan,Bin Yu,Hong‐Min Liu.Advanced Synthesis & Catalysis . 2019 (1)
[3] Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor[J] . Zhong-Rui Li,Feng-Zhi Suo,Bo Hu,Yan-Jia Guo,Dong-Jun Fu,Bin Yu,Yi-Chao Zheng,Hong-Min Liu.Bioorganic Chemistry . 2018
[4] Discovery of a Non-toxic[1,2,4]Triazolo[1,5-A]Pyrimidin-7-One (WS-10) that Modulates ABCB1-Mediated Multidrug Resistance (MDR)[J] . Liming Chang,Mengwu Xiao,Linlin Yang,Shuai Wang,Sai-Qi Wang,Andreas Bender,Aixi Hu,Zhe-Sheng Chen,Bin Yu,Hong-Min Liu.Bioorganic & Medicinal Chemistry . 2018
[5] Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo[J] . Zhiqiang Zhang,Xiaoran Guo,Kenneth K.W. To,Zhen Chen,Xiaona Fang,Min Luo,Chunling Ma,Jianhua Xu,Shirong Yan,Liwu Fu.Acta Pharmaceutica Sinica B . 2018
[6] Mechanisms of resistance to EGFR tyrosine kinase inhibitors[J] . Lihua Huang,Liwu Fu.Acta Pharmaceutica Sinica B . 2015 (5)
[7] Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor[J] . Xu Zhang,Ting Peng,Xun Ji,Jian Li,Linjiang Tong,Zeng Li,Wei Yang,Yungen Xu,Mengyuan Li,Jian Ding,Hualiang Jiang,Hua Xie,Hong Liu.Bioorganic & Medicinal Chemistry . 2013 (24)
[8] Shared Risk Evaluation Mitigation Strategy for all Immediate-Release Transmucosal Fentanyl Dosage Forms[J] . Food and Drug Administration,Public Health Service,U.S. Department of Health and Human Services.Journal of Pain and Palliative Care Pharmacothera . 2012 (2)
[9] Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: Implications for the emergence and reversal of cancer drug resistance[J] . Biochemical Pharmacology . 2012 (3)
[10] Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies[J] . Fenlai Tan,Xiaoyan Shen,Dechang Wang,Guojian Xie,Xiaodong Zhang,Lieming Ding,Yunyan Hu,Wei He,Yanping Wang,Yinxiang Wang.Lung Cancer . 2011 (2)

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