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

基本信息

批准号：
8238648
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238648
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 Delivery Systems 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 Screening procedure 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 small molecule structural biology success tool tumor ubiquitin-protein ligase validation studies

项目摘要

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. PUBLIC HEALTH RELEVANCE: Enzymes known as E3 ubiquitin ligases have been linked in many ways to cancer. For example, the Mdm2 E3 ligase is amplified or overexpressed in 7% of all human cancers, and is estimated to impact 100,000 new patients every year in the U.S. alone. However, the discovery of drugs that inhibit these enzymes remains an unmet challenge. This proposal is aimed at discovering small molecule inhibitors of Mdm2 that can be developed into novel therapies.

描述（由申请人提供）：最近，蛋白酶体抑制剂（硼替佐米）在治疗血癌中的成功验证了针对肿瘤药物发现的靶向蛋白质降解途径。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。我们开发了一种合理且独特的策略来识别新的候选药物，这些候选药物在蛋白质降解途径中比蛋白酶体更具选择性。我们将利用该通路上游的一类酶（称为 E3 泛素连接酶）进行药物抑制——由于每种 E3 作用的底物比蛋白酶体少得多，因此我们预计将开发出毒性较小的药物。尽管 E3 抑制剂作为药物靶点具有巨大潜力，但发现 E3 抑制剂并将其引入临床仍然面临着尚未解决的挑战。为了实现这些目标，我们设计了一种创新方法，旨在鉴定 Mdm2 抑制剂，Mdm2 是肿瘤抑制蛋白 p53 的主要 E3 连接酶——已知 Mdm2 抑制会导致细胞中 p53 蛋白水平增加，预计具有药理学相关性。我们发现的 Mdm2 抑制剂将接受早期药物开发的概念验证研究。具体来说，在对 Mdm2 抑制剂进行基于靶标的生化筛选后，表现出理想的药物样特征并且比其他 E3 连接酶具有选择性的最有效的命中将进行初步的药物化学研究。然后，将表征表现最佳的化合物类似物引发预测的生物和治疗效果的能力。最后，我们将利用生化和结构生物学方法研究其 E3 抑制机制，然后进行第二轮药物化学和验证研究。相关性：Mdm2 癌蛋白已被广泛验证为肿瘤药物靶点。它在 7% 的人类癌症中被扩增或过度表达，估计仅在美国每年就会影响 100,000 名新患者。然而，目前还没有针对 Mdm2 或其他 E3 连接酶的药物进入临床试验或上市。因此，具有抗肿瘤特性的 Mdm2 E3 连接酶活性抑制剂的发现将代表着癌症治疗药物开发的重大创新。公共健康相关性：被称为 E3 泛素连接酶的酶在很多方面与癌症有关。例如，Mdm2 E3 连接酶在 7% 的人类癌症中扩增或过度表达，预计仅在美国每年就会影响 100,000 名新患者。然而，抑制这些酶的药物的发现仍然是一个未解决的挑战。该提案旨在发现可开发成新疗法的 Mdm2 小分子抑制剂。