Small Molecule Inhibitors of Mdm2 E3 Ubiquitin Ligase Activity for Cancer Therapy

Mdm2 E3 泛素连接酶活性的小分子抑制剂用于癌症治疗

• 批准号: 8815096
• 负责人: CLAUDIO A.P. JOAZEIRO
• 金额: $ 39.32万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815096
• 关键词: Address; Adverse effects; Affect; Binding; Biochemical; Biological; Biological Assay; Bortezomib; Cancer Patient; Cancer cell line; Cells; Clinic; Clinical Trials; Collection; DNA Damage; Degradation Pathway; Development; Drug Targeting; Drug resistance; Enzymes; Exhibits; Future; Galactosidase; Goals; Grant; Health; Hematopoietic Neoplasms; Human; Industry; Knowledge; Lead; Left; Link; Malignant Neoplasms; Marketing; Measures; Mediating; Mono-S; Mutation; Names; Oncogene Proteins; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology and Toxicology; Physiology; Problem Solving; Process; Property; Proteasome Inhibitor; Protein p53; Proteins; Reaction; Reporter; Research; Research Personnel; Resistance development; Role; Running; Selection Bias; Signal Pathway; Source; Staging; Structure; System; Testing; Therapeutic; Therapeutic Effect; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Validation; Work; Xenograft procedure; analog; base; cancer cell; cancer therapy; cytotoxicity; design; drug candidate; drug development; drug discovery; experience; improved; inhibitor/antagonist; innovation; interest; multicatalytic endopeptidase complex; mutant; novel; oncology; overexpression; polypeptide; pre-clinical; protein degradation; reconstitution; response; screening; small molecule; structural biology; success; tool; tumor; ubiquitin-protein ligase; validation studies

DESCRIPTION (provided by applicant): Targeting protein degradation pathways for Oncology drug discovery has recently been validated by the success of the proteasome inhibitor (bortezomib) in the treatment of blood cancers. However, bortezomib has side effects, and cancer patients can also develop resistance to the drug. We have developed a rationale and unique strategy to identify new drug candidates that act more selectively than the proteasome in protein degradation pathways. We will exploit a class of enzymes upstream in the pathway, known as E3 ubiquitin ligases, for drug inhibition-since each E3 acts on much fewer substrates than the proteasome, we expect less toxic drugs to be developed. Despite their great potential as drug targets, discovering and bringing E3 inhibitors to the clinic have remained unmet challenges. To achieve these goals, we have designed an innovative approach with the aim to identify inhibitors of Mdm2, the main E3 ligase for the tumor suppressor protein p53 --Mdm2 inhibition is known to cause an increase in p53 protein levels in cells and is expected to be pharmacologically relevant. The Mdm2 inhibitors we find will then undergo proof-of-concept studies for early-stage drug development. Specifically, following target-based biochemical screens for Mdm2 inhibitors, the most potent hits that exhibit desirable drug-like features and are selective over other E3 ligases will undergo initial medicinal chemistry efforts. Top-performing compound analogs will then be characterized for the ability to elicit the predicted biological and therapeutic effects. Finally, we will investigate their mechanism of E3 inhibition using biochemical and structural biology approaches, followed by a second round of medicinal chemistry and validation studies. Relevance: The Mdm2 oncoprotein has been widely validated as an oncology drug target. It is amplified or overexpressed in 7% of all human cancers, estimated to impact 100,000 new patients every year in the U.S. alone. However, no drugs targeting Mdm2 or other E3 ligases are currently in clinical trials or in the market. The discovery of inhibitors of Mdm2 E3 ligase activity with anti-tumor properties will thus represent a significant innovation in the development of drugs for the treatment of cancer.

描述（由申请人提供）：最近，蛋白酶体抑制剂（硼替佐米）在血癌治疗中的成功验证了肿瘤药物发现的靶向蛋白降解途径。然而，硼替佐米有副作用，癌症患者也会对该药物产生耐药性。我们已经开发了一种原理和独特的策略来鉴定在蛋白质降解途径中比蛋白酶体更具选择性的新候选药物。我们将利用一类酶上游的途径，被称为E3泛素连接酶，药物抑制，因为每个E3的作用比蛋白酶体少得多的底物，我们预计毒性较小的药物开发。尽管E3抑制剂作为药物靶点具有巨大的潜力，但发现并将其应用于临床仍然是一个尚未解决的挑战。为了实现这些目标，我们设计了一种创新的方法，目的是鉴定Mdm 2的抑制剂，Mdm 2是肿瘤抑制蛋白p53的主要E3连接酶-Mdm 2抑制已知会导致细胞中p53蛋白水平的增加，并且预计与肿瘤相关。我们发现的Mdm 2抑制剂将进行早期药物开发的概念验证研究。具体而言，在对Mdm 2抑制剂进行基于靶标的生化筛选之后，表现出期望的药物样特征并且对其他E3连接酶具有选择性的最有效的命中物将经历初始的药物化学努力。然后将表征表现最好的化合物类似物引起预测的生物学和治疗效果的能力。最后，我们将使用生物化学和结构生物学方法研究它们抑制E3的机制，然后进行第二轮药物化学和验证研究。相关性：Mdm 2癌蛋白已被广泛验证为肿瘤学药物靶点。它在7%的人类癌症中被扩增或过表达，仅在美国每年就有10万新患者受到影响。然而，目前没有靶向Mdm 2或其他E3连接酶的药物处于临床试验或市场中。因此，具有抗肿瘤特性的Mdm 2 E3连接酶活性抑制剂的发现将代表用于治疗癌症的药物开发中的重大创新。