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Novel calcium signaling pathways in cell cycle regulations

细胞周期调节中的新型钙信号通路

基本信息

批准号：
09044282
负责人：
NIKI Ichiro
金额：
$ 3.26万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

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.

在我们两年的合作中，我们广泛讨论了创造各种蛋白激酶的新型和选择性抑制剂的可能性。去年10月在名古屋举行的第70届日本生化学会年会上，l.m.发表了部分成果。我们共同感兴趣的是，异喹啉-磺胺衍生物是否对细胞周期相关激酶的活性有任何抑制作用，因为一些异喹啉-磺胺化合物，如H-7，可以被视为“一般激酶抑制剂”。因此，我们试图从多种异喹啉化合物中寻找cdc2-激酶抑制剂。在几个被调查的化合物中，H-1152及其衍生物确实被发现在低muM浓度下抑制cdc2激酶。然而，这些抑制剂既不具有选择性，也不像l.m.r oomoucine或roscovitine那样作为异嘌呤化合物，这表明它们的相关抑制机制可能是不同的，尽管异喹啉和异嘌呤化合物都表现出atp竞争性抑制。另一个有趣的问题是，这些atp竞争化合物的抑制效力是否仅仅反映了每种蛋白激酶对atp的需求，因为这种可能性与异喹啉-磺苯酰胺抑制剂（H-7和HA-1077）对rho激酶的抑制有关。然而，在评估了这些化合物对其他具有不同atp需求的蛋白激酶的作用后，最终证明情况并非如此。这是设计新型蛋白激酶抑制剂及其临床应用的关键。