title: TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis.
abstract: TOPK (T-lymphokine-activated killer cell-originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer cells. We report the development of a potent TOPK inhibitor, OTS964 {(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one}, which inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Our results suggest that the inhibition of TOPK activity may be a viable therapeutic option for the treatment of various human cancers.
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa 213-0012, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa 213-0012, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa 213-0012, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Kanagawa 213-0012, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Hisada
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Houda
authors.initials: H
authors.lastname: Alachkar
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. ynakamura@bsd.uchicago.edu.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases