Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer

Oncotarget. 2012 Dec;3(12):1629-40. doi: 10.18632/oncotarget.790.


We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC₅₀ of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. This MELK inhibitor should be a promising compound possibly to suppress the growth of tumor-initiating cells and be applied for treatment of a wide range of human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Female
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Injections, Intravenous
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Microfilament Proteins / metabolism
  • Molecular Structure
  • Molecular Targeted Therapy*
  • NIH 3T3 Cells
  • Naphthyridines / administration & dosage*
  • Naphthyridines / chemistry
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemistry
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • src Homology Domains


  • 1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
  • Antineoplastic Agents
  • DBNL protein, human
  • Microfilament Proteins
  • Naphthyridines
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • MELK protein, human
  • Protein Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex