Small Molecules that Regulate Proteasome Activity

调节蛋白酶体活性的小分子

• 批准号: 7748967
• 负责人: Chin-Ho Chen
• 金额: $ 30.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748967
• 关键词: Amino Acids; Antineoplastic Agents; Betulinic Acid; Binding; Biological Factors; Bortezomib; Cancer cell line; Cell Cycle; Cell model; Cell physiology; Chemical Structure; Chemicals; Collection; Disease; Drug Binding Site; Drug Delivery Systems; Exhibits; Goals; Growth; Hand; Huntington Disease; Induction of Apoptosis; Inhibition of Cell Proliferation; Label; Lead; Malignant Neoplasms; Mediating; Modification; Molecular; Molecular Probes; Molecular Target; Neoplasm Metastasis; Neurodegenerative Disorders; Neurons; Pharmaceutical Preparations; Pharmacologic Substance; Play; Process; Proteasome Inhibition; Proteasome Inhibitor; Proteolysis; Role; Screening procedure; Side; Structure-Activity Relationship; System; Terpenes; Testing; Therapeutic; Ubiquitin; angiogenesis; base; cancer cell; cancer therapy; cancer type; cell type; design; drug candidate; drug discovery; human disease; improved; inhibitor/antagonist; interest; multicatalytic endopeptidase complex; nervous system disorder; next generation; novel; public health relevance; scaffold; small molecule; tool; tumor; tumor growth

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.

描述（由申请人提供）：泛素-蛋白酶体系统在调节细胞周期、癌症生长和转移中起重要作用。蛋白酶体的活化是最佳蛋白水解活性所需的关键过程。蛋白酶体的抑制剂显示出阻止肿瘤生长、肿瘤扩散和血管生成。另一方面，药物样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有着巨大的兴趣，但目前临床上只有一种蛋白酶体抑制剂，即硼替佐米，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，如白桦脂酸，激活蛋白酶体，白桦脂酸的化学修饰使其成为蛋白酶体抑制剂。我们推测，有效的蛋白酶体激活剂或抑制剂可以从萜类天然产物中鉴定出来，并且它们的效力可以通过化学修饰进一步增加。通过实现以下具体目标，将实现该目标并验证该假设：1）发现激活或抑制蛋白酶体的新萜类化合物; 2）通过先导物优化获得下一代有效的蛋白酶体抑制剂; 3）确定萜类化合物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小组的萜类化合物和策略的铅优化，以实现我们的目标，在发现有效的蛋白酶体激活剂和抑制剂，可以调节蛋白酶体活性在低纳摩尔或亚纳摩尔浓度。预计在完成拟定研究后，将确定一类新的新型蛋白酶体调节剂（激活剂和抑制剂）和抑制剂的分子靶点。此外，该研究还将确定所提出的蛋白酶体调节剂对癌症和亨廷顿病等疾病的治疗潜力。新的蛋白酶体激活剂和抑制剂的发现将不仅提供一个非常有用的工具，解剖蛋白酶体介导的细胞功能的分子机制，但也有可能被开发为治疗疾病，如癌症的治疗。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。这些化合物有可能在治疗上用于治疗有害的人类疾病，例如癌症和神经退行性疾病。