Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China; School of Basic Medical Sciences and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, 637000, China.
Eur J Med Chem. 2022 Aug 5;238:114446. doi: 10.1016/j.ejmech.2022.114446. Epub 2022 May 11.
AlkB homolog 5 (ALKBH5) is an RNA mA demethylase involved in the regulation of genes transcription, translation and metabolism and has been considered as a promising therapeutic target for various human diseases, especially cancers. However, there is still a lack of potent and selective ALKBH5 inhibitors. Herein, we report a new class of ALKBH5 inhibitors containing the 1-aryl-1H-pyrazole scaffold, which were obtained through fluorescence polarization-based screening, structural optimization and structure-activity relationship analysis. Among these compounds, 20m was the most potent one, which showed an IC value of 0.021 μM in fluorescence polarization assay. Compound 20m exhibited high selectivity towards ALKBH5 versus FTO as well as other AlkB subfamily members, indicating good selectivity for ALKBH5. Cellular thermal shift assay (CETSA) analysis showed that 20m could efficiently stabilize ALKBH5 in HepG2 cells. Dot blot assay demonstrated that 20m could increase mA level in intact cells. Collectively, 20m is a potent, selective and cell active ALKBH5 inhibitor and could be used as a versatile chemical probe to explore the biological function of ALKBH5.
ALKBH5 同源物 5（ALKBH5）是一种 RNA mA 去甲基酶，参与基因转录、翻译和代谢的调控，已被认为是治疗各种人类疾病，特别是癌症的有前途的治疗靶点。然而，仍然缺乏有效的、选择性的 ALKBH5 抑制剂。在此，我们报告了一类包含 1-芳基-1H-吡唑骨架的新型 ALKBH5 抑制剂，这些抑制剂是通过基于荧光偏振的筛选、结构优化和构效关系分析获得的。在这些化合物中，20m 是最有效的一种，在荧光偏振测定中其 IC 值为 0.021 μM。化合物 20m 对 ALKBH5 具有高选择性，相对于 FTO 以及其他 AlkB 亚家族成员具有良好的选择性，表明对 ALKBH5 具有良好的选择性。细胞热转移分析（CETSA）分析表明，20m 能够在 HepG2 细胞中有效地稳定 ALKBH5。点印迹分析表明，20m 能够增加完整细胞中的 mA 水平。总之，20m 是一种有效、选择性和细胞活性的 ALKBH5 抑制剂，可作为一种通用的化学探针，用于探索 ALKBH5 的生物学功能。
