DEVELOPMENT OF TYPE II INHIBITORS FOR JNK3

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在帕金森-S病小鼠模型中，抑制JNK3已被证明可以保护小鼠免受多巴胺能神经元丢失的影响。到目前为止，I型ATP竞争性抑制剂已经被设计并成功结晶。然而，晶体结构是处理非活性蛋白质的，而对结合到蛋白质活性形式上的抑制物的翻译尚不清楚。MAP激酶家族中II型抑制剂的发现为我们计划研究的JNK3酶的非活性形式开辟了一条新的靶点。我们认为，这条途径将允许增加激酶和可能的JNK异构体特异性，而更传统的I型抑制剂缺乏。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.