2. Academic Validation
  3. Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1

Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1

  • J Am Chem Soc. 2024 Mar 13;146(10):6992-7006. doi: 10.1021/jacs.4c00194.
Liang Xiong 1 2,  Feng Li 1 2,  Yinping Guo 1 2,  Jian Zhang 1 2,  Ke Xu 3,  Zijie Xiong 1 2,  Aiping Tong 1,  Linli Li 3,  Shengyong Yang 1 2
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 38437718 DOI: 10.1021/jacs.4c00194
Abstract

N6-Methyladenine (6mA) of DNA has emerged as a novel epigenetic mark in eukaryotes, and several 6mA effector proteins have been identified. However, efforts to selectively inhibit the biological functions of these effector proteins with small molecules are unsuccessful to date. Here we report the first potent and selective small molecule inhibitor (13h) of AlkB homologue 1 (ALKBH1), the only validated 6mA demethylase. 13h showed an IC50 of 0.026 ± 0.013 μM and 1.39 ± 0.13 μM in the fluorescence polarization (FP) and Enzyme activity assay, respectively, and a KD of 0.112 ± 0.017 μM in the isothermal titration calorimetry (ITC) assay. The potency of 13h was well explained by the cocrystal structure of the 13h-ALKBH1 complex. Furthermore, 13h displayed excellent selectivity for ALKBH1. In cells, compound 13h and its derivative 16 were able to engage ALKBH1 and modulate the 6mA levels. Collectively, our study identified the first potent, isoform selective, and cell-active ALKBH1 inhibitor, providing a tool compound for exploring the biological functions of ALKBH1 and DNA 6mA.

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