Small Molecules that Regulate Proteasome Activity

描述（申请人提供）：泛素-蛋白酶体系统在调节细胞周期、肿瘤生长和转移中起重要作用。蛋白酶体的激活是最佳蛋白水解活性所必需的关键过程。蛋白酶体的抑制剂被证明可以抑制肿瘤生长、肿瘤扩散和血管生成。另一方面，类似药物的蛋白酶体激活剂是罕见的，其生物医学应用仍有待确定。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硼替佐米（Bortezomib）可用于抗癌治疗。本研究的目的是鉴定和合成能够特异性和有效地抑制或激活蛋白酶体的小分子。我们的初步结果表明，萜类天然产物，如白桦酸，可以激活蛋白酶体，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剂，并且可以通过化学修饰进一步提高它们的效力。通过实现以下具体目标，将实现目标并对假设进行检验：1)发现激活或抑制蛋白酶体的新萜类；2)通过先导优化获得新一代强效蛋白酶体抑制剂；3)确定萜类蛋白酶体抑制剂的药物结合位点和作用方式。我们已经建立了一个萜类化合物小组和先导优化策略，以实现我们的目标，即发现有效的蛋白酶体激活剂和抑制剂，可以在低纳摩尔或亚纳摩尔浓度下调节蛋白酶体活性。预计在完成拟议的研究后，一类新的蛋白酶体调节因子（激活剂和抑制剂）和抑制剂的分子靶点将被确定。此外，该研究还将确定拟议的蛋白酶体调节因子对癌症和亨廷顿病等疾病的治疗潜力。发现新的蛋白酶体激活剂和抑制剂不仅为剖析蛋白酶体介导的细胞功能的分子机制提供了非常有用的工具，而且也有可能被开发为治疗癌症等疾病的疗法。公共卫生相关性：该项目的主要目标是开发小分子蛋白酶体抑制剂和激活剂。这些化合物在治疗癌症和神经退行性疾病等有害人类疾病方面具有潜在的治疗作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE:The major goal of this project is to develop small molecule proteasome inhibitors and activators. These compounds have potential to be therapeutically useful for treating detrimental human diseases such as cancers and neurodegenerative disorders.