A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein

Bioorg Med Chem. 2025 Jul 1:124:118178. doi: 10.1016/j.bmc.2025.118178. Epub 2025 Mar 29.

Abstract

The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.

Keywords: Cinnamic acid derivatives; Hepatocellular carcinoma; METTL16.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cinnamates* / chemical synthesis
  • Cinnamates* / chemistry
  • Cinnamates* / pharmacology
  • Cinnamates* / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Methyltransferases* / antagonists & inhibitors
  • Methyltransferases* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Cinnamates
  • cinnamic acid
  • Methyltransferases
  • METTL16 protein, human