Optimization and Biological Evaluation of Novel 1H-Pyrrolo[2,3-c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia

被引:0
|
作者
Jiang, Hong [1 ,2 ,3 ]
Li, Cong [7 ]
Li, Na [2 ,3 ,4 ,5 ]
Sheng, Li [7 ]
Wang, Jingkai [1 ,2 ,3 ]
Kan, Wei-Juan [7 ]
Chen, Yuelei [2 ]
Zhao, Dongmei [1 ]
Guo, Dong [6 ]
Zhou, Yu-Bo [7 ,8 ]
Xiong, Bing [2 ,3 ,9 ]
Li, Jia [7 ,8 ,9 ]
Liu, Tongchao [2 ,3 ]
机构
[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
[4] Lingang Lab, Shanghai 200031, Peoples R China
[5] ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 200031, Peoples R China
[6] Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou 221004, Jiangsu Provinc, Peoples R China
[7] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[8] Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
[9] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
基金
中国国家自然科学基金;
关键词
LSD1; INHIBITORS; DESIGN;
D O I
10.1021/acs.jmedchem.4c02017
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Lysine-specific demethylase 1 (LSD1) plays a vital role in the epigenetic regulation of various cancers, making it a promising therapeutic target for anticancer treatments. Herein, we designed and synthesized a novel series of 1H-pyrrolo[2,3-c]pyridin derivatives as potent LSD1 inhibitors. A detailed structure-activity relationship exploration was carried out to discover multiple derivatives with nanomolar enzymatic IC50 values. Further biological evaluation demonstrated that these compounds acted as selective and reversible LSD1 inhibitors. The representative compounds exhibited highly potent antiproliferative activity against both AML (MV4-11 and Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively activated CD86 mRNA expression in MV4-11 cells and induced differentiation of AML cell lines. Notably, the most promising compound 23e showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound 23e as a lead compound for developing LSD1 inhibitors for the treatment of AML and other advanced malignancies.
引用
收藏
页码:22080 / 22103
页数:24
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