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Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors

文献类型：期刊论文

作者Li, Chunpu2,3,4; Su, Mingbo5; Zhu, Wei2; Kan, Weijuan2; Ge, Tianpeng2,6; Xu, Gaoya2; Wang, Shuni2; Sheng, Li2; Gao, Feng2; Ye, Yunfei7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-03-10
卷号65期号:5页码:4335-4349
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c02156
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要LSD1 is identified as an essential drug target, which is closely correlated to the development of several tumor types. In this work, on the basis of comprehensive analysis of the binding site of LSD1 and other FAD-dependent enzymes, a novel series of potent and selective LSD1 inhibitors were designed by incorporation of privileged indoline scaffold strategies. Representative compound 7e (LSD1; IC50 = 24.43 nM, selectivity over LSD2 and MAOs of >200- and 4000-fold) possessed selective antiproliferative activities against MV-4-11 cell lines. Further study indicates that 7e could activate CD86 expression (EC50 = 470 nM) and induce differentiation of AML cell lines. More importantly, compound 7e demonstrated an acceptable oral PK profile and good in vivo antitumor efficacy with a T/C value of 30.89% in an MV-4-11 xenograft mouse model. Collectively, this work provides a promising lead compound for the development of novel LSD1 inhibitors for the treatment of AML.
WOS关键词MONOAMINE-OXIDASE-A ; TRANYLCYPROMINE ; DISCOVERY ; DESIGN ; POTENT
资助项目National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81620108027] ; SA-SIBS Scholarship Program ; Youth Innovation Promotion Association CAS[2020282] ; Lingang Laboratory[LG202103-02-06]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000772205900035
源URL[http://119.78.100.183/handle/2S10ELR8/299888]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Liu, Hong
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Weifang Med Univ, Coll Pharm, Weifang 261053, Peoples R China
7.China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China
推荐引用方式
GB/T 7714		 Li, Chunpu,Su, Mingbo,Zhu, Wei,et al. Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(5):4335-4349.
APA Li, Chunpu.,Su, Mingbo.,Zhu, Wei.,Kan, Weijuan.,Ge, Tianpeng.,...&Liu, Hong.(2022).Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,65(5),4335-4349.
MLA Li, Chunpu,et al."Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 65.5(2022):4335-4349.

入库方式： OAI收割

来源：上海药物研究所

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