| Co-Investigator(Kenkyū-buntansha) |
MEIJER Laurent Center National de la Recherche Scientifique, Station Biologique, Professor, 教授
NAITO Yasuhito School of Medicine, Research Associate, 医学部, 助手 (80303618)
WATANABE Yasuo School of Medicine, Assistant Professor, 医学部, 講師 (10273228)
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| Research Abstract |
During our two-year collaboration, we have extensively discussed the possibility to create novel and selective inhibitors of various protein kinases. A part of the result was presented by L.M.in a symposium of the 7lth Annual meeting of Japanese Biochemical Society held in Nagoya last October. Our mutual interest was whether isoquinoline-sulphonamide derivatives exhibit any inhibition on the activities of cell-cycle-related kinases, because some of the isoquinoline-sulphonamide compounds such as H-7 could be regarded as 'general kinase inhibitors'. Therefore, we attempted to look for a cdc2-kinase inhibitor from a variety of isoquinoline compounds. Among several compounds surveyed, H-1152 and its derivatives were, indeed, found to inhibit cdc2 kinase at low muM concentrations. However, these inhibitors were neither selective nor potent as isopurine compounds as olomoucine or roscovitine developed by L.M.This suggests to us that their relevant mechanisms of inhibition may be distinct, although both isoquinoline and isopurine compounds exhibited ATP-competitive inhibition. Another interest was whether potency of the inhibition by these ATP-competitive compounds may simply reflect a ATP-requirement of each protein kinase, because this possibility was implicated in inhibition of Rho-kinase by isoquinoline-suiphonamide inhibitors (H-7 and HA-1077). Eventually it was proved that such was, however, not the case after evaluation of the effects of these compounds against other protein kinases with different ATP-requirements. This is a crucial point to design novel protein kinase inhibitors and their application to a clinical use.
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