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.