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Updated: Jan 16, 2026
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Identification of novel small molecule inhibitors targeting multiple methyltransferase like proteins against
Md Niaz Morshed1,2, Sorwer Alam Parvez2,3, Rakibul Islam Akanda2
1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA.
Abstract:
The development of more efficient and durable multi-targeted therapeutic drug against hepatocellular carcinoma (HCC) has recently been of growing interest to tackle chemoresistance. Several studies indicate that increased expression of methyltransferase-like (METTL) proteins, including METTL1, METTL3, METTL6, METTL16, and METTL18, are associated with the progression of HCC malignancy, making them potential biomarkers. Here, using a series of computer-aided drug design (CADD) approaches, we identified two first-in-class highly potent catalytic multi-target inhibitors (ZINC70666503 and ZINC13000658 with 87% and 82% predicted drug scores, respectively) of these five methyltransferase-like proteins. The molecular dynamics study supported their conformational stability with these METTL proteins and high selectivity at the pocket of proteins' adenosine moiety of S-Adenosyl Methionine. Further in vitro experiments revealed significant anti-proliferative activity and effects on the cell cycle of ZINC13000658 against two HCC cell lines, HepG2 and SNU-449. This work provides evidence that multitargeted METTL may have stronger inhibition of HCC cell proliferation. Further in vivo validation, toxicity analysis as well as molecular insights will determine the therapeutic utility against HCC.
Insights
Researchers identified novel multi-target inhibitors for hepatocellular carcinoma (HCC) by targeting methyltransferase-like (METTL) proteins. These compounds show significant anti-proliferative effects in HCC cells, offering new therapeutic potential against this cancer.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Hepatocellular carcinoma (HCC) presents challenges due to chemoresistance.
- Increased expression of methyltransferase-like (METTL) proteins (METTL1, METTL3, METTL6, METTL16, METTL18) correlates with HCC malignancy.
- METTL proteins are potential therapeutic targets and biomarkers for HCC.
Purpose of the Study:
- To identify novel, potent, multi-targeted inhibitors for METTL proteins implicated in HCC.
- To evaluate the anti-proliferative efficacy of identified inhibitors against HCC cell lines.
- To explore the potential of targeting multiple METTL proteins for HCC treatment.
Main Methods:
- Employed computer-aided drug design (CADD) approaches to screen for inhibitors.
- Utilized molecular dynamics simulations to assess inhibitor stability and selectivity.
- Conducted in vitro experiments to determine anti-proliferative activity and cell cycle effects on HCC cell lines (HepG2, SNU-449).
Main Results:
- Identified two first-in-class catalytic multi-target inhibitors: ZINC70666503 (87% predicted score) and ZINC13000658 (82% predicted score).
- Molecular dynamics confirmed conformational stability and high selectivity for the S-Adenosyl Methionine binding pocket of METTL proteins.
- ZINC13000658 demonstrated significant anti-proliferative activity and affected the cell cycle in HepG2 and SNU-449 HCC cell lines.
Conclusions:
- Multi-targeted inhibition of METTL proteins shows promise for stronger inhibition of HCC cell proliferation.
- The identified compounds, particularly ZINC13000658, represent potential first-in-class therapeutics for HCC.
- Further in vivo validation and toxicity analyses are necessary to establish the therapeutic utility of these METTL inhibitors against HCC.
