Structural Optimization and Structure-Activity Relationship of 1 H -Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity.

Autor: Li F; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Xiong L; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Zhang J; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Guo Y; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Xu K; Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China., Xiong Z; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Wang Y; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Ji S; Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China., Tong A; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China., Li L; Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China., Yang S; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.; New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Sep 12; Vol. 67 (17), pp. 15456-15475. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1021/acs.jmedchem.4c01072
Abstrakt: DNA N 6 -methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1 H -pyrazole-4-carboxylic acid derivative 29 . The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29 , we prepared a prodrug of 29 ( 29E ), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E . Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.
Databáze: MEDLINE
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