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

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

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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）：靶向肿瘤药物发现的蛋白质降解途径最近通过蛋白酶体抑制剂（Bortezomib）在血液癌症治疗中的成功验证。但是，硼替佐米具有副作用，癌症患者也可以对药物产生抗性。我们已经制定了一种基本原理和独特的策略，可以鉴定出比蛋白质降解途径中蛋白酶体更有选择性的新药候选者。我们将利用该途径上游的一类酶，称为E3泛素连接酶，用于药物抑制作用，每个E3的作用于蛋白酶体的底物少得多，我们期望开发毒性较小的药物。尽管它们作为药物靶标的潜力很大，但发现并将E3抑制剂带到诊所仍然是未满足的挑战。为了实现这些目标，我们设计了一种创新的方法，目的是识别MDM2的抑制剂，已知肿瘤抑制蛋白p53 -MDM2抑制的主要E3连接酶会导致细胞中p53蛋白水平的升高，并且预计有药理学相关。然后，我们发现的MDM2抑制剂将进行早期药物开发的概念验证研究。具体而言，遵循MDM2抑制剂的基于目标的生化筛选，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打击将进行最初的药物化学努力。然后，最佳表现的化合物类似物的特征是引起预测的生物学和治疗作用的能力。最后，我们将使用生化和结构生物学方法研究其E3抑制的机制，然后进行第二轮药物化学和验证研究。相关性：MDM2癌蛋白已被广泛证实为肿瘤药物靶标。在所有人类癌症中，有7％的人在7％的人中会放大或过表达它，仅在美国，每年就会影响100,000名新患者。但是，目前没有针对MDM2或其他E3连接酶的药物正在临床试验或市场中。因此，发现具有抗肿瘤特性的MDM2 E3连接酶活性的抑制剂将代表用于治疗癌症药物的发展的重要创新。公共卫生相关性：称为E3泛素连接酶的酶已与许多方式联系在一起。例如，在所有人类癌症中，MDM2 E3连接酶在7％的7％中被放大或过表达，并且据估计，仅在美国，每年就会影响100,000名新患者。但是，抑制这些酶的药物的发现仍然是一个未得到的挑战。该建议旨在发现可以发展为新疗法的MDM2的小分子抑制剂。