MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel.
Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.
Shimomura
Toshiyasu
T
Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Ibaraki, Japan. toshiyasu_shimomura@merck.com
Hasako
Shinichi
S
Nakatsuru
Yoko
Y
Mita
Takashi
T
Ichikawa
Koji
K
Kodera
Tsutomu
T
Sakai
Takumi
T
Nambu
Tadahiro
T
Miyamoto
Mayu
M
Takahashi
Ikuko
I
Miki
Satomi
S
Kawanishi
Nobuhiko
N
Ohkubo
Mitsuru
M
Kotani
Hidehito
H
Iwasawa
Yoshikazu
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000077143:Docetaxel; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D043823:Taxoids / Q000494:pharmacology* / Q000633:toxicity; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D000970:Antineoplastic Agents; D003509:Cyclohexanecarboxylic Acids; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases