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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

文献类型：期刊论文

作者Jiang, Hong2,3,4; Li, Cong7; Li, Na1,3,4,5; Sheng, Li7; Wang, Jingkai2,3,4; Kan, Wei-Juan7; Chen, Yuelei3; Zhao, Dongmei2; Guo, Dong6; Zhou, Yu-Bo7,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-12-04
卷号67期号:24页码:22080-22103
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02017
英文摘要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.
WOS关键词LSD1 INHIBITORS ; DESIGN
资助项目National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[81773572] ; National Natural Science Foundation of China[82204187] ; National Natural Science Foundation of China ; Program for Innovative Research Team of the Ministry of Education ; Program for Liaoning Innovative Research Team in University
WOS研究方向Pharmacology & Pharmacy
WOS记录号WOS:001370328900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/314989]  
专题新药研究国家重点实验室
通讯作者Zhao, Dongmei; Li, Jia; Liu, Tongchao
作者单位1.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 200031, Peoples R China
2.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Lingang Lab, 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
推荐引用方式
GB/T 7714		 Jiang, Hong,Li, Cong,Li, Na,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(24):22080-22103.
APA Jiang, Hong.,Li, Cong.,Li, Na.,Sheng, Li.,Wang, Jingkai.,...&Liu, Tongchao.(2024).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.JOURNAL OF MEDICINAL CHEMISTRY,67(24),22080-22103.
MLA Jiang, Hong,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 67.24(2024):22080-22103.

入库方式： OAI收割

来源：上海药物研究所

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