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 1,2; Du, Juanjuan 3; Ye, Fei 4; Chen, Zhifeng5 ; Li, Lianchun 6,7; Lian, Fulin 1,2; Zhang, Bidong 1,2; Zhang, Yuanyuan 1,2; Jiang, Hualiang 1,2; Chen, Kaixian1,5 ; Li, Yuanchao 3; Zhou, Bing 3; Zhang, Naixia 1; Yang, Yaxi 3; Luo, Cheng 1,5
	2016
发表期刊	ORGANIC & BIOMOLECULAR CHEMISTRY (IF:2.9[JCR-2023],2.8[5-Year])
ISSN	1477-0520
卷号	14 期号:36 页码:8503-8519
发表状态	已发表
DOI	10.1039/c6ob01248e
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.
收录类别	SCI ; IC ; EI
语种	英语
资助项目	CAS Strategic Priority Research Program[XDA12020333]
WOS研究方向	Chemistry
WOS类目	Chemistry, Organic
WOS记录号	WOS:000384313100013
出版者	ROYAL SOC CHEMISTRY
EI入藏号	20163902839200
EI主题词	Chemical analysis ; Chemical modification ; Diseases ; Integrated circuits ; Molecules
EI分类号	Semiconductor Devices and Integrated Circuits:714.2 ; Organic Compounds:804.1 ; Atomic and Molecular Physics:931.3
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
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2008
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_陈凯先组生命科学与技术学院_硕士生
通讯作者	Zhang, Yuanyuan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 4.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China 5.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, 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.