2. Academic Validation
  3. Identification of novel small molecule inhibitors targeting multiple methyltransferase like proteins against hepatocellular carcinoma

Identification of novel small molecule inhibitors targeting multiple methyltransferase like proteins against hepatocellular carcinoma

  • Sci Rep. 2025 Sep 26;15(1):33087. doi: 10.1038/s41598-025-16614-0.
Md Niaz Morshed 1 2,  Sorwer Alam Parvez 2 3,  Rakibul Islam Akanda 2,  Manash Kumar Saha 2,  Jannatul Fardous 4,  Maksudul Alam 1,  Yunfeng Zhao 5,  Omar E Franco 6,  Mohammad Jakir Hosen 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA.
  • 2 Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
  • 3 Department of Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA.
  • 4 Chittagong Medical College, Chittagong University, Chittagong, Bangladesh.
  • 5 Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA.
  • 6 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA. omar.francocoronel@lsuhs.edu.
  • 7 Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh. jakir-gen@sust.edu.
PMID: 41006418 DOI: 10.1038/s41598-025-16614-0
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.

Keywords

Drug repurposing; Hepatocellular carcinoma; Methyltransferase inhibitor; Multi-target drug design; Pharmacophore modeling.

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