1,4-Naphthoquinones as inhibitors of Itch, a HECT domain-E3 ligase, and tumor growth suppressors in multiple myeloma

Eur J Med Chem. 2017 Nov 10:140:84-91. doi: 10.1016/j.ejmech.2017.09.011. Epub 2017 Sep 6.

Abstract

A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma.

Keywords: HECT domain E3 ligase inhibitor; Naphthoquinone.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Molecular Structure
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / pathology
  • Naphthoquinones / chemical synthesis
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Repressor Proteins
  • Structure-Activity Relationship
  • Ubiquitin-Protein Ligases

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Naphthoquinones
  • Repressor Proteins
  • ITCH protein, human
  • Ubiquitin-Protein Ligases
  • 1,4-naphthoquinone