title: Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR.
abstract: This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n . Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Wenteng
authors.initials: W
authors.lastname: Chen
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Jiaan
authors.initials: J
authors.lastname: Shao
authors.affiliation: School of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Biqin
authors.initials: B
authors.lastname: Tan
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Chunchun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Hu
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Deng
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd. , Building 5, No. 898 Ha Lei Road, Shanghai, China ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , Hangzhou 310058, P. R. China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
keywords: Anticancer; EGFR; conformationally constrained; kinase inhibitor