2. Academic Validation
  3. 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

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

  • J Med Chem. 2024 Sep 12;67(17):15456-15475. doi: 10.1021/acs.jmedchem.4c01072.
Feng Li 1 2,  Liang Xiong 1 2,  Jian Zhang 1 2,  Yinping Guo 1 2,  Ke Xu 3,  Zijie Xiong 1 2,  Yuyang Wang 1 2,  Shanmian Ji 3,  Aiping Tong 1,  Linli Li 3,  Shengyong Yang 1 2
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 39225755 DOI: 10.1021/acs.jmedchem.4c01072
Abstract

DNA N6-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, 1H-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.

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