Small-molecule Inhibitors of Wee1 Degradation and Mitotic Entry

我们的长期目标是了解有丝分裂进入的基本机制和机制， 细胞增殖了解细胞增殖在产生癌症治疗中是必不可少的，因为许多 癌细胞无法控制地复制。细胞增殖的一个基本特征是不可逆的， 控制其细胞周期转换的性质。这些转变的组成部分是泛素介导的蛋白水解 靶向蛋白酶体降解底物的途径。蛋白水解途径包括E1、E2和E3 调节降解事件的时间和保真度的酶。虽然我们已经确定了许多 这些途径的组成部分，我们仍然有一个不完整的了解蛋白质是如何靶向 降解蛋白酶体靶向的时间和调节都不清楚。这是特别 在有丝分裂进入的情况下是正确的。一种在S期和G2期抑制有丝分裂的蛋白质 在细胞周期的各个阶段，细胞被降解以启动有丝分裂进入。我们的目标是阐明这是如何发生的 一种特殊的蛋白质被转换以启动有丝分裂。我们将使用生物化学和细胞生物学方法， 理解细胞降解和有丝分裂进入。我们将开发一种高通量的测定方法来测量井 细胞内降解。我们将确定筛选后获得的化合物是否对韦尔有特异性。 此外，我们将确定是否相同的化合物也抑制有丝分裂进入。认识的重要性 影响weel降解的成分被发现在某些细胞中过表达所强调， 癌的 与公共卫生的相关性：需要阐明细胞增殖途径以产生新的 癌症治疗学蛋白酶体降解途径的抑制剂目前被用于治疗 某些癌症包括多发性骨髓瘤。

Our long term objectives are to understand the basic machinery and mechanism of mitotic entry and cell proliferation. Understanding cell proliferation is essential in generating cancer therapy since many cancer cells replicate uncontrollably. An essential feature of cell proliferation is the irreversible and controlled nature of its cell cycle transitions. Integral to these transitions are ubiquitin mediated proteolytic pathways that target substrates for proteasomal degradation. Proteolytic pathways contain E1, E2, and E3 enzymes that regulate both the timing and fidelity of degradation events. While we have identified many components of these pathways, we still have an incomplete understanding of how proteins are targeted for degradation. Both the timing and regulation of proteasomal targeting is not understood. This is especially true in the case of the mitotic entry. One of the proteins involved in inhibiting mitosis during the S and G2 phases of the cell cycle, weel, is degraded to initiate mitotic entry. Our goals are to elucidate how this particular protein is turned over to initiate mitosis. We will use a biochemical and cell biological approach to understand weel degradation and mitotic entry. We will develop a high through put assay to measure weel degradation in cells. We will determine if the compounds we attain after screening are specific for weel. Furthermore, we will determine if the same compounds also inhibit mitotic entry. The importance of known components affecting weel degradtion is underscored by the finding that they are overexpressed in certain cancers. Relevance to public health: The elucidation of cell proliferation pathways is required for generating novel cancer therapeutics. An inhibitor of the proteasome degradation pathway is currently being used to treat certain cancers including multiple myeloma.