Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide

doi:10.1039/c6ob01248e

	Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide
	Yue, Liyan 2,3; Du, Juanjuan 4; Ye, Fei 5; Chen, Zhifeng 1; Li, Lianchun 6,7; Lian, Fulin 2,3; Zhang, Bidong 2,3; Zhang, Yuanyuan 2,3; Jiang, Hualiang2,3 ; Chen, Kaixian1,2
刊名	ORGANIC & BIOMOLECULAR CHEMISTRY
	2016
卷号	14 期号:36 页码:8503-8519
ISSN号	1477-0520
DOI	10.1039/c6ob01248e
文献子类	Article
英文摘要	Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the meninMLL interaction (IC50 = 69 +/- 3 mu M). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 +/- 0.13 mu M, 0.69 +/- 0.07 mu M and 0.66 +/- 0.05 mu M, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.
资助项目	National Basic Research Program[2015CB910304] ; Hi-Tech Research and Development Program of China[2014AA01A302] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81202398] ; National Natural Science Foundation of China[81402849] ; National Natural Science Foundation of China[21272246] ; Zhejiang Province Natural Science Foundation[LQ14H300003] ; Public Projects of Zhejiang Province[2015C33159] ; Zhejiang Provincial Top Key Discipline of Biology[00000000] ; CAS Strategic Priority Research Program[XDA12020333]
WOS关键词	MIXED-LINEAGE LEUKEMIA ; PROTEIN-PROTEIN INTERACTION ; DRUG DISCOVERY ; HISTONE MODIFICATIONS ; BIOLOGICAL EVALUATION ; CANCER EPIGENETICS ; ACCURATE DOCKING ; FUSION PROTEINS ; HYBRID APPROACH ; IN-VIVO
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000384313100013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276200]
专题	分析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药物发现与设计中心药物化学研究室
通讯作者	Zhang, Yuanyuan
作者单位	1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 5.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China; 6.Guangxi Inst Bot, Guangxi Key Lab Funct Phytochem Res & Utilizat, Guilin 541006, Guangxi Zhuang, Peoples R China; 7.Chinese Acad Sci, Guilin 541006, Guangxi Zhuang, Peoples R China
推荐引用方式 GB/T 7714	Yue, Liyan,Du, Juanjuan,Ye, Fei,et al. Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2016,14(36):8503-8519.
APA	Yue, Liyan.,Du, Juanjuan.,Ye, Fei.,Chen, Zhifeng.,Li, Lianchun.,...&Luo, Cheng.(2016).Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide.ORGANIC & BIOMOLECULAR CHEMISTRY,14(36),8503-8519.
MLA	Yue, Liyan,et al."Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide".ORGANIC & BIOMOLECULAR CHEMISTRY 14.36(2016):8503-8519.