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Discovery of maleimide derivatives as m6A demethylase ALKBH5 inhibitors

Luxia Liang1, Wenlong Fei1, Yingzhe Wang1

  • 1State Key Laboratory of Natural Medicines and Jiangsu 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.

Bioorganic & Medicinal Chemistry
|February 4, 2025
PubMed

Insights

Researchers discovered novel maleimide-based small molecules that inhibit Human AlkB homologue H5 (ALKBH5), a key enzyme in mRNA modification. Compound 18 shows promise as a potential ALKBH5 inhibitor for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Human AlkB homologue H5 (ALKBH5) is a critical enzyme responsible for the demethylation of N6-methyladenosine (m6A) in mRNA.
  • m6A modification plays a significant role in gene expression regulation and is implicated in various cancers, including acute myeloid leukemia (AML).
  • Despite ALKBH5 being a recognized therapeutic target in oncology, the development of specific ALKBH5 inhibitors has been limited.

Purpose of the Study:

  • To identify and develop novel small molecule inhibitors targeting ALKBH5.
  • To explore the potential of maleimide-based compounds as ALKBH5 inhibitors.
  • To establish a lead compound for further preclinical development.

Main Methods:

  • Design and synthesis of a series of maleimide-based compounds.
  • In vitro screening and evaluation of synthesized compounds for ALKBH5 inhibitory activity.
  • Optimization of lead compounds to enhance potency and selectivity.

Main Results:

  • Discovery of a series of maleimide-based small molecule inhibitors of ALKBH5.
  • Identification of compound 18 as a potent ALKBH5 inhibitor following structure-activity relationship optimization.
  • Compound 18 demonstrated significant potential as a lead compound for ALKBH5-targeted therapies.

Conclusions:

  • Maleimide derivatives represent a promising scaffold for the development of ALKBH5 inhibitors.
  • Compound 18 is a valuable starting point for the development of novel therapeutics targeting ALKBH5 in cancer.
  • Further investigation into compound 18 is warranted to explore its therapeutic efficacy in preclinical cancer models.
Keywords:
ALKBH5FTOInhibitorsM(6)A

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