Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR

doi:10.1021/ml4002437

	Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR
	Wu, Jianwei 2; Chen, Wenteng 2; Xia, Guangxin 3; Zhang, Jing 3; Shao, Jiaan 2; Tan, Biqin 1; Zhang, Chunchun 3; Yu, Wanwan 2; Weng, Qinjie 1; Liu, Haiyan 3
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	2013-10
卷号	4 期号:10 页码:974-978
关键词	Anticancer kinase inhibitor EGFR conformationally constrained
ISSN号	1948-5875
DOI	10.1021/ml4002437
文献子类	Article
英文摘要	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, A.549, and 1(562). 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.
资助项目	National Natural Science Foundation of China[81072516] ; National Natural Science Foundation of China[81273356] ; Natural Science Foundation of Zhejiang Province[Z2110655] ; Program for Zhejiang Leading Team of ST Innovation[00000000] ; Osteoporosis and Breast Cancer Research Center, USA[00000000]
WOS关键词	GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITORS ; NEUTRAL 5-SUBSTITUTED 4-ANILINOQUINAZOLINES ; ORALLY-ACTIVE INHIBITORS ; LUNG-CANCER MODELS ; IRREVERSIBLE INHIBITORS ; THERAPY ; POTENT ; HER-2
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000326367200019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277433]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Shen, Jingkang
作者单位	1.Zhejiang Univ, Sch Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China; 2.Zhejiang Univ, Zhejiang Prov Key Lab Anticanc Drug Res, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China; 3.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, Shanghai, Peoples R China; 4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wu, Jianwei,Chen, Wenteng,Xia, Guangxin,et al. Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR[J]. ACS MEDICINAL CHEMISTRY LETTERS,2013,4(10):974-978.
APA	Wu, Jianwei.,Chen, Wenteng.,Xia, Guangxin.,Zhang, Jing.,Shao, Jiaan.,...&Yu, Yongping.(2013).Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR.ACS MEDICINAL CHEMISTRY LETTERS,4(10),974-978.
MLA	Wu, Jianwei,et al."Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR".ACS MEDICINAL CHEMISTRY LETTERS 4.10(2013):974-978.