Fei Wen-Long, Wang Ying-Zhe, Feng Qing-Lan, Li Cui-Ting, Jiang Rui-Xin, Zhang Shi-Di, Pan Yun, Ni Peng-Fei, Huang Fei-Ran, Huangfu Yi-Bing, Zhang Shi-Da, You Qi-Dong, Guo Xiao-Ke
State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug, Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug, Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2025 Feb 15;284:117183. doi: 10.1016/j.ejmech.2024.117183. Epub 2024 Dec 23.
N-methyladenosine (mA) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for mA and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5. Herein, we designed and synthesized the ALKBH5 covalent inhibitor DDO-02267 by analyzing the protein structure of ALKBH5 and introducing salicylaldehyde warhead into noncovalent small molecule ligand. DDO-02267 specifically targeted Lys132 within ALKBH5, demonstrating significant selectivity for ALKBH5 in vitro. Additionally, DDO-02267 increased mA levels and targeted the ALKBH5-AXL signaling axis in AML cells. The compound DDO-02267 can serve as a probe for investigating the biological function of mRNA demethylase and may inspire the development of future ALKBH5 inhibitors.
N-甲基腺苷（mA）是真核生物中一种关键的mRNA表观遗传修饰，其甲基化调控与多种肿瘤细胞的增殖和转移相关。ALKBH5作为mA的去甲基化酶，在去甲基化过程中发挥作用，从而影响肿瘤细胞的生长和迁移。然而，关于ALKBH5选择性小分子抑制剂的报道有限。在此，我们通过分析ALKBH5的蛋白质结构并将水杨醛弹头引入非共价小分子配体，设计并合成了ALKBH5共价抑制剂DDO-02267。DDO-02267特异性靶向ALKBH5内的赖氨酸132，在体外对ALKBH5表现出显著的选择性。此外，DDO-02267提高了mA水平，并靶向急性髓系白血病（AML）细胞中的ALKBH5-AXL信号轴。化合物DDO-02267可作为研究mRNA去甲基化酶生物学功能的探针，并可能推动未来ALKBH5抑制剂的开发。
