Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

doi:10.1039/c7md00571g

	Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors
	Chen, Deheng 1,2; Guo, Dexiang 1; Yan, Ziqin 1; Zhao, Yujun1
刊名	MEDCHEMCOMM
	2018-02
卷号	9 期号:2 页码:244-253
ISSN号	2040-2503
DOI	10.1039/c7md00571g
文献子类	Article
英文摘要	The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, 14, inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. 14 also inhibited the growth of NCI-H1975 lung cancer cells at IC50 = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with 14. By measuring the conjugate addition product formed by 14 and GSH, we obtained a reaction rate constant of 302.5 x 10(-3) min(-1), which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.
资助项目	Chinese Academy of Sciences[XDA12020322] ; National Natural Science Foundation of China[81673295] ; Shanghai Institute of Materia Medica startup-grant[00000000] ; Recruitment Program of Global Youth Experts (The 1000 Youth Talents Program)[00000000]
WOS关键词	FACTOR RECEPTOR THREONINE(790) ; LUNG-CANCER ; BIOLOGICAL EVALUATION ; EGFR INHIBITORS ; IRREVERSIBLE INHIBITORS ; METHIONINE(790) MUTANT ; KINASE INHIBITORS ; TYROSINE KINASES ; DRUG DESIGN ; DISCOVERY
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000426487200005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279918]
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	Zhao, Yujun
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Deheng,Guo, Dexiang,Yan, Ziqin,et al. Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors[J]. MEDCHEMCOMM,2018,9(2):244-253.
APA	Chen, Deheng,Guo, Dexiang,Yan, Ziqin,&Zhao, Yujun.(2018).Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors.MEDCHEMCOMM,9(2),244-253.
MLA	Chen, Deheng,et al."Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors".MEDCHEMCOMM 9.2(2018):244-253.