Small-molecule Inhibitors of Wee1 Degradation and Mitotic Entry

描述（由申请人提供）：我们的长期目标是了解有丝分裂进入和细胞增殖的基本机制和机制。了解细胞增殖对于产生癌症治疗至关重要，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其细胞周期转换的不可逆性和受控性。这些转变的组成部分是泛素介导的蛋白水解途径，其靶向蛋白酶体降解的底物。蛋白水解途径包含E1、E2和E3酶，这些酶调节降解事件的时间和保真度。虽然我们已经确定了这些途径的许多组成部分，但我们仍然不完全了解蛋白质是如何被降解的。蛋白酶体靶向的时间和调节都不清楚。在有丝分裂进入的情况下尤其如此。在细胞周期的S期和G2期参与抑制有丝分裂的蛋白质之一，weel，被降解以启动有丝分裂进入。我们的目标是阐明这种特殊的蛋白质是如何转变为启动有丝分裂的。我们将使用生物化学和细胞生物学的方法来了解细胞降解和有丝分裂进入。我们将开发一种高通量测定法来测量细胞中的weel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。已知的影响细胞降解的组分的重要性通过它们在某些癌症中过表达的发现而得到强调。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疗法。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。

DESCRIPTION (provided by applicant): 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 degradation 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.