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

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Structural Optimization and Structure–Activity Relationship of 1H-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-03 , 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}

Affiliation

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.

中文翻译：

1H-吡唑-4-羧酸衍生物作为DNA 6mA去甲基化酶ALKBH1抑制剂的结构优化、构效关系及其抗胃癌活性

DNA N ^{6 -}甲基腺嘌呤 (6mA) 去甲基酶 ALKBH1 在各种细胞过程中发挥着重要作用。 ALKBH1 的失调与某些癌症类型（包括胃癌）的发生有关，暗示着潜在的治疗靶点。然而，仍然缺乏有效的 ALKBH1 抑制剂。在此，我们报告发现了一种高效的 ALKBH1 抑制剂，1 H -吡唑-4-羧酸衍生物29 。还讨论了该系列化合物的构效关系。由于29的细胞膜渗透性较差，我们制备了29的前药（ 29E ），其表现出优异的细胞活性。在胃癌细胞系 HGC27 和 AGS 中， 29E处理显着增加了 6mA 的丰度，抑制了细胞活力，并上调了 AMP 激活蛋白激酶 (AMPK) 信号通路。此外，在给予29E后，水解产物29在小鼠中显示出高暴露。总的来说，这项研究提供了一种新的有效的 ALKBH1 抑制剂，可以作为后续药物开发的先导化合物。

更新日期：2024-09-03

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