DEVELOPMENT OF TYPE II INHIBITORS FOR JNK3

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The inhibition of JNK3 has been shown to protect mice from the dopaminergic neuronal cell loss associated in the mouse model of Parkinson?s disease. To date, Type I ATP competitive inhibitors have been designed and successfully crystallized. However, the crystal structures are dealing with inactive protein and the exact understanding of the translation of the inhibitor binding onto the active form of the protein is unknown. The discovery of Type II inhibitors in the MAP kinase family opened up a novel way to specifically target the inactive form of the enzyme which we plan on examining with respect to JNK3. We feel that this path will allow for the increase in kinase and possibly JNK isoform specificity lacking in a more traditional Type I inhibitor.