2. Academic Validation
  3. Discovery of a Novel Selective and Cell-Active N6-Methyladenosine RNA Demethylase ALKBH5 Inhibitor

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

  • J Med Chem. 2025 Feb 27;68(4):4133-4147. doi: 10.1021/acs.jmedchem.4c01542.
Xianyuan Yang 1,  Kaitao Huang 1,  Xu-Nian Wu 1,  Chen Zhang 2,  Yixuan Sun 3,  Yanfeng Gao 3,  Jiawang Zhou 1,  Lijun Tao 1,  Haisheng Zhang 1,  Yinuo Wu 1,  Hai-Bin Luo 4,  Hongsheng Wang 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 2 School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering and Technology Research Center, Guangdong Pharmaceutical University, Zhongshan, Guangdong 528458, China.
  • 3 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen Campus, Shenzhen 518107, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
PMID: 39925002 DOI: 10.1021/acs.jmedchem.4c01542
Abstract

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.

Figures
Products