Small Molecules that Regulate Proteasome Activity

标题：调节蛋白酶体活性的小分子 泛素-蛋白酶体系统在调节细胞周期、肿瘤生长和 转移。蛋白酶体的激活是蛋白水解酶最佳活性所必需的关键过程。 蛋白酶体的抑制剂被证明可以阻止肿瘤生长、肿瘤扩散和血管生成。论 另一方面，类药物蛋白酶体激活剂很少，它们在生物医学上的应用还有待于进一步研究。 下定决心。尽管人们对开发针对蛋白酶体的药物非常感兴趣，但目前 临床上只有一种蛋白酶体抑制剂Bortezomib可用于抗癌治疗。这样做的目的是 研究是识别和合成能够特异性和有效地抑制或激活细胞外基质的小分子 蛋白酶体。我们的初步结果表明，桦木酸等萜类天然产物具有活性 蛋白酶体，并对白桦酸进行化学修饰，使其成为蛋白酶体抑制剂。我们 假设可以从萜类天然产物中鉴定出有效的蛋白酶体激活剂或抑制物 而且它们的效力可以通过化学修饰进一步提高。这一目标将会实现，而 假说将通过实现以下具体目标来检验：1)发现新的具有活性的萜类化合物 或抑制蛋白酶体；2)通过铅获得下一代有效的蛋白酶体抑制剂 优化；3)确定萜类蛋白酶体抑制剂的药物结合部位和作用方式。 我们已经建立了一组萜类化合物和先导优化策略，以实现我们在 发现能在低浓度下调节蛋白酶体活性的有效蛋白酶体激活剂和抑制剂 纳摩尔或亚纳摩尔浓度。预计一类新型的蛋白酶体调控因子 (激活剂和抑制剂)和抑制剂的分子靶标将在完成 建议进行的研究。此外，这项研究还将确定拟议的 蛋白酶体对癌症和亨廷顿病等疾病的调节作用。小说的发现 蛋白酶体激活剂和抑制物不仅为剖析分子提供了一个非常有用的工具 蛋白酶体介导的细胞功能的机制，但也有可能被开发为 治疗癌症等疾病的治疗学。

Title: Small molecules that regulate proteasome activity The ubiquitin-proteasome system plays an important role in regulating the cell cycle, cancer growth, and metastasis. Activation of the proteasome is a critical process that is required for optimal proteolytic activity. Inhibitors of the proteasome were shown to arrest tumor growth, tumor spread, and angiogenesis. On the other hand, drug-like proteasome activators are rare, and their biomedical applications remain to be determined. Although there is tremendous interest in developing drugs targeting the proteasome, currently there is only one clinically available proteasome inhibitor, Bortezomib, for anti-cancer therapy. The goal of this study is to identify and synthesize small molecules that can specifically and potently inhibit or activate the proteasome. Our preliminary results indicated that terpenoid natural products, such as betulinic acid, activated proteasome, and chemical modifications on betulinic acid turned it into proteasome inhibitors. We hypothesize that potent proteasome activators or inhibitors could be identified from terpenoid natural products and their potency can be further increased by chemical modifications. The goal will be achieved and the hypothesis will be tested by carrying out the following specific aims: 1) to discover new terpenoids that activate or inhibit the proteasome; 2) to obtain a next generation of potent proteasome inhibitors through lead optimization; 3) to determine the drug binding site and mode of action of the terpenoid proteasome inhibitors. We have established a panel of terpenoids and the strategies for lead optimization to achieve our goal in the discovery of potent proteasome activators and inhibitors that can regulate the proteasome activity at low nanomolar or sub-nanomolar concentrations. It is expected that a new class of novel proteasome regulators (activators and inhibitors) and the molecular target of the inhibitor will be identified upon completion of the proposed studies. Moreover, the study will also determine the therapeutic potential of the proposed proteasome regulators for diseases such as cancers and Huntington's disease. Discovery of novel proteasome activators and inhibitors would not only provide a very useful tool for dissecting the molecular mechanisms of proteasome-mediated cellular functions, but would also have the potential to be developed as therapeutics to treat diseases such as cancers.