Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor

doi:10.1016/j.bmcl.2019.126825

	Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor
	Hu, Chujiao 2; Zuo, Yu 1; Liu, Jingqiu 3; Xu, Heng 3; Liao, Weike 2; Dang, Yongjun 4; Luo, Cheng 3; Tang, Lei 2; Zhang, Hao 3
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2020-01-15
卷号	30 期号:2 页码:5
关键词	Licochalcone A Mutant IDH1 Selective inhibitor
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2019.126825
通讯作者	Tang, Lei(tlei1974@163.com) ; Zhang, Hao(hao_cadd@simm.ac.cn)
英文摘要	IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia. By screening dozens of reported natural compounds using both wild-type and mutant IDH1 enzymatic assays, we discovered Licochalcone A is a selective inhibitor to the R132C-mutant IDH1 with an IC50 value of 5.176 mu M, and inhibits the proliferation of sarcoma HT-1080 cells with an IC50 value of 10.75 mu M. Suggested by the molecular docking results, Licochalcone A might occupy the allosteric pocket between the two monomers of IDH1 homodimer, and the R132H mutation was unfavorable for the binding of Licochalcone A with the IDH1 protein, as compared to the R132C mutation. Revealed by the RNA-Seq data analysis, the Cell Cycle pathway was the most over-represented pathway for HT-1080 cells treated with Licochalcone A. Consistent with these results, Licochalcone A induced apoptosis and cell cycle arrest of HT-1080 cells, while it showed minimal effect against the proliferation of normal RCTEC cells. The discovery of Licochalcone A as a mutation-selective IDH1 inhibitor can serve as a promising starting point for the development of mutation-selective anti-tumor lead compounds targeting IDH1.
资助项目	National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120184015] ; National-Local Joint Engineering Research Center for Innovative & Generic Chemical Drug, Guizhou High-level Innovative Talents Supporting Program[2016-4015] ; Shanghai Young Science and Technology Talents Sailing Plan[19YF1457200]
WOS关键词	GANODERMA-LUCIDUM ; MUTATIONS
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000504873300027
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282345]
专题	中国科学院上海药物研究所
通讯作者	Tang, Lei; Zhang, Hao
作者单位	1.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China 2.Guizhou Medcial Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550014, Guizhou, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Hu, Chujiao,Zuo, Yu,Liu, Jingqiu,et al. Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2020,30(2):5.
APA	Hu, Chujiao.,Zuo, Yu.,Liu, Jingqiu.,Xu, Heng.,Liao, Weike.,...&Zhang, Hao.(2020).Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,30(2),5.
MLA	Hu, Chujiao,et al."Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 30.2(2020):5.