PT  - JOURNAL ARTICLE
AU  - Matsuo, Yo
AU  - Park, Jae-Hyun
AU  - Miyamoto, Takashi
AU  - Yamamoto, Shinji
AU  - Hisada, Shoji
AU  - Alachkar, Houda
AU  - Nakamura, Yusuke
TI  - TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis
AID  - 10.1126/scitranslmed.3010277
DP  - 2014 Oct 22
TA  - Science Translational Medicine
PG  - 259ra145--259ra145
VI  - 6
IP  - 259
4099  - http://stm.sciencemag.org/content/6/259/259ra145.short
4100  - http://stm.sciencemag.org/content/6/259/259ra145.full
AB  - 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.