RRC ID 44220
著者 Chung S, Suzuki H, Miyamoto T, Takamatsu N, Tatsuguchi A, Ueda K, Kijima K, Nakamura Y, Matsuo Y.
タイトル Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer.
ジャーナル Oncotarget
Abstract 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.
巻・号 3(12)
ページ 1629-40
公開日 2012-12-1
DOI 10.18632/oncotarget.790
PII 790
PMID 23283305
PMC PMC3681500
MeSH 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
IF 5.168
引用数 90
WOS 分野 ONCOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞