Discovery of the salicylaldehyde-based compound DDO-02267 as a lysine-targeting covalent inhibitor of ALKBH5

• Published in: European journal of medicinal chemistry Vol. 284; pp. 117183 - 117200
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2025; Elsevier
• Subjects: Aldehydes - chemistry; Aldehydes - pharmacology; AlkB Homolog 5, RNA Demethylase - antagonists & inhibitors; AlkB Homolog 5, RNA Demethylase - metabolism; ALKBH5; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Chemistry, Medicinal; Covalent inhibitor; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Lysine - chemistry; Lysine - metabolism; M6A; Molecular Structure; Pharmacology & Pharmacy; Salicylaldehyde warhead; Science & Technology; Structure-Activity Relationship; Salicylaldehyde warhead; M6A; ALKBH5; Covalent inhibitor; DEMETHYLASE; CELLS; KINASE INHIBITORS; MA
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.117183

N6-methyladenosine (m6A) 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 m6A 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 m6A 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. [Display omitted] •Structure-guided design and optimization yield potent ALKBH5 covalent inhibitors.•DDO-02267 binds to Lys132 residue, thereby inhibiting ALKBH5 enzyme activity.•Targeting Lys132 is a viable strategy for designing ALKBH5 covalent inhibitors.