Human AlkB homologue H5 (ALKBH5) is a crucial demethylase for N⁶-methyladenosine (m⁶A) of mRNA. Although ALKBH5 is recognized as a promising target in various cancers, especially acute myeloid leukemia (AML), research on inhibitors of ALKBH5 remains limited. Here, we reported the discovery of a series of maleimide-based small molecule inhibitors of ALKBH5, resulting in the identification of compound 18 through optimization. Comprehensive evaluations suggested that compound 18 holds significant potential as a lead compound for ALKBH5 inhibitor.

27 Feb 2025·Journal of Medicinal Chemistry

Discovery of a Novel Selective and Cell-Active N⁶-Methyladenosine RNA Demethylase ALKBH5 Inhibitor

Article

Author: Sun, Yixuan ; Yang, Xianyuan ; Wu, Xu-Nian ; Zhou, Jiawang ; Luo, Hai-Bin ; Wu, Yinuo ; Gao, Yanfeng ; Wang, Hongsheng ; Zhang, Haisheng ; Huang, Kaitao ; Zhang, Chen ; Tao, Lijun

N⁶-methyladenosine (m⁶A), the most abundant methylation on mRNA, plays pivotal roles in regulating mRNA biological functions, which affect cell functions. ALKBH5, an m⁶A demethylase, was found to be an oncogene in several cancer types, including triple-negative breast cancer (TNBC). Here, we report a novel and selective ALKBH5 covalent inhibitor, W23-1006, through virtual screening and structure optimization. It covalently bonds to the ALKBH5 C200 residue with an IC₅₀ value of 3.848 μM, representing roughly 30- and 8-fold stronger inhibitory activity than that against FTO and ALKBH3, respectively. Cellular experiments demonstrated that W23-1006 could efficiently enhance the m⁶A level on fibronectin 1 (FN1) mRNA, leading to strong suppression of TNBC cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Collectively, our study developed a novel, selective, and cell-active ALKBH5 covalent inhibitor, W23-1006, which could be a potential therapeutic option for cancer, such as TNBC treatment.

01 Feb 2025·European Journal of Medicinal Chemistry

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

Article

Author: Jiang, Rui-Xin ; Wang, Ying-Zhe ; Zhang, Shi-Di ; You, Qi-Dong ; Huangfu, Yi-Bing ; Fei, Wen-Long ; Pan, Yun ; Feng, Qing-Lan ; Ni, Peng-Fei ; Guo, Xiao-Ke ; Zhang, Shi-Da ; Huang, Fei-Ran ; Li, Cui-Ting

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.

100 Deals associated with ALKBH5 inhibitor(Shanghai Institute of Materia Medica Chinese Academy of Sci)

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	Preclinical	China	Shanghai Institute of Materia Medica Chinese Academy of Sci	20 Feb 2025

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ALKBH5 inhibitor(Shanghai Institute of Materia Medica Chinese Academy of Sci)

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