Molecular basis and generation of new compounds for probing phosphorylation-mediated signaling pathways

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Evidence accum ulated that protein kinases are involved in a variety of cellular processes such as depolarization -coupled smooth muscle contraction, secretagogues-stimulated release of biologically active substances from secretory cells, and mitogen-activated cell growth. Protein kinase inhibitors seem to be usful in studying physiological significance of protein kinases and part of tham probably works as medicines. This hypothesis has been, if any, proved with our H-series protein kinase inhibitors, H-89, H-7, KN-62, and HA-1077. Our goal of this research is to elucidate their actions and to construct some theory for molecular designing of protein kinase inhibitors. The results obtained are summarized as described below.1. The crystal structure of protein kinase A complex with H-7,8,89 was deterimined (Bossmeyer et. al. JBC,1996). This revealed that the adenine pocket of the protein accommodates well the isoquinokinesulfonamide of H-series compounds. It seems likely that the degree t … More o which the chemical structure added to the isoquinokinesulfonamide contributes to binding of the compounds determines their selectivity for protein kinases.2. HA-1077 shows a non-specific inhibition for a variety of protein kinases including myosin light chain kinase and is used as medicine for the treatment of cerebral vasospasm after subarachnoidal hemorrhage. By addition of some chemical groups to HA-1077, for example its methylation, such new compounds were found to change remarkably into specific inhibitors of some protein kinase. Combined with the findings described above, it is possible to amend H-series compounds by altering their chemical groups attached to the isoquinolinesulfonamide core.3. Based on structure-activity relationship, it was found that an isoquinolinesulfonamide was also indispensable for KN-62 to show calcium/calmodulin-dependent protein kinase inhibition, although the compound competed with calmodulin, but not with ATP.We consider that H-series compounds are seed compounds for new protein kinase inhibitors, and that they will bear more fruits when more information conceruing the structures of protein kinases are available. Less