Developing Chemical Probes to Decipher Gankyrin Biology

抽象的。Gankyrin是一种癌蛋白，在多种癌症类型中过度表达，似乎起着关键作用 在调节细胞增殖、细胞迁移和上皮-间充质转化中起重要作用。这些角色主要是由于 与甘结蛋白众多的蛋白质间相互作用有关。这些蛋白质-蛋白质相互作用的重要性 证明是通过降低gankyrin的表达水平或直接扰乱其蛋白质-蛋白质 相互作用，导致细胞增殖、细胞迁移和上皮-间充质减少 在多种癌症类型的动物模型中，过渡以及疾病严重程度。因此，甘菊一直是 在多种癌症类型中被认为是一种耐人寻味的蛋白质。然而，甘草蛋白对细胞的调节作用 对细胞增殖、细胞迁移和上皮-间充质转化知之甚少。这个项目的总体目标是 建议进一步开发我们的gankyrin靶向探针，可以用来破译gankyrin的大部分 调控癌细胞增殖、迁移和上皮-间充质转化的生物学作用。 此外，这些探针将有助于验证甘草蛋白作为治疗靶点，因为它在 多种癌症类型。为了实现这一目标，我们正在寻求提高cjoc42支架的能力。 结合甘草蛋白，提高基于特定细胞的检测效率。这项提案还将寻求提供 有关Gankyrin在癌症生物学中作用的初步数据，但主要重点将是开发和验证我们的 在未来的实验中有用的探头。最终，这项提案将提供所需的化学探针，以充分 了解甘结蛋白的生物学作用将直接影响多发性癌症的治疗进展 类型。

Abstract. Gankyrin is an oncoprotein overexpressed in numerous cancer types and appears to play key roles in regulating cell proliferation, cell migration and epithelial-mesenchymal transition. These roles are primarily due to gankyrin’s numerous protein-protein interactions. The importance of these protein-protein interactions has been demonstrated by either decreasing gankyrin expression levels or directly disrupting its protein-protein interactions, which has resulted in decreased cell proliferation, cell migration and epithelial-mesenchymal transition, as well as disease severity in animal models of numerous cancer types. Therefore, gankyrin has been identified as an intriguing protein in multiple cancer types. However, much of how gankyrin regulates cell proliferation, cell migration and epithelial-mesenchymal transition is poorly understood. The overall goal of this proposal is to further develop our gankyrin-targeting probes which can be utilized to decipher much of gankyrin’s biological role in regulating cancer cell proliferation, migration and epithelial-mesenchymal transition. Furthermore, these probes will help in validating gankyrin as a therapeutic target due to its diverse roles in multiple cancer types. In order to achieve this goal, we are seeking to improve the ability of the cjoc42 scaffold to bind gankyrin and increase efficacy in specific cell-based assays. This proposal will also seek to provide preliminary data about gankyrin’s role in cancer biology, but the primary focus will be to develop and validate our probes as useful in future experiments. Ultimately, this proposal will provide the chemical probes required to fully understand gankyrin’s biological roles which will directly impact therapeutic advancements in multiple cancer types.