Anticancer peptide therapeutics

抗癌肽疗法

基本信息

批准号：
9518796
负责人：
WUYUAN LU
金额：
$ 35.34万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9518796
关键词：
Acute Myelocytic Leukemia Affinity Antibodies Antineoplastic Agents Apoptotic Binding Cancer Patient Cancerous Cell physiology Cells Cellular Stress Cessation of life Chemistry Clinical Clinical Treatment Colon Carcinoma Country DNA Damage DNA Sequence Alteration Development Discipline Disease Disease remission Drug Industry Drug Targeting Expenditure Funding Goals Growth Health Care Costs Hematopoietic Homologous Gene Human Impairment In Vitro Intervention Laboratories Lead MDM2 gene Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Modality Molecular Target Molecular Weight Monoclonal Antibodies Mus Mutate Mutation Mutation Analysis Myeloid Cells Normal Cell Pathway interactions Patients Peptide Hydrolases Peptide antibodies Peptides Pharmaceutical Preparations Pharmacology Play Pluripotent Stem Cells Predisposition Primary Neoplasm Property Protein p53 Proteins Proteolysis Recombinants Relapse Research Resistance Role Runaway Running Series Side Signal Pathway Specificity Structure Survival Rate TP53 gene Techniques Testing Therapeutic Transactivation Transplantation Treatment Efficacy Tumor Cell Line Tumor Suppressor Proteins Uterine Cancer X-Ray Crystallography anti-cancer anti-cancer therapeutic antibody conjugate base cancer cell cancer therapy cell injury chemotherapy design drug discovery genotoxicity improved in vivo inhibitor/antagonist innovation leukemia leukemia treatment malignant breast neoplasm malignant stomach neoplasm molecular targeted therapies nanomolar neoplastic cell new therapeutic target novel novel therapeutics overexpression peptide L peptide drug prevent protein protein interaction rare cancer research and development response transcription factor trend tumor tumor growth tumorigenesis ubiquitin-protein ligase uptake weapons

Acute Myelocytic Leukemia Affinity Antibodies Antineoplastic Agents Apoptotic Binding Cancer Patient Cancerous Cell physiology Cells Cellular Stress Cessation of life Chemistry Clinical Clinical Treatment Colon Carcinoma Country DNA Damage DNA Sequence Alteration Development Discipline Disease Disease remission Drug Industry Drug Targeting Expenditure Funding Goals Growth Health Care Costs Hematopoietic Homologous Gene Human Impairment In Vitro Intervention Laboratories Lead MDM2 gene Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Modality Molecular Target Molecular Weight Monoclonal Antibodies Mus Mutate Mutation Mutation Analysis Myeloid Cells Normal Cell Pathway interactions Patients Peptide Hydrolases Peptide antibodies Peptides Pharmaceutical Preparations Pharmacology Play Pluripotent Stem Cells Predisposition Primary Neoplasm Property Protein p53 Proteins Proteolysis Recombinants Relapse Research Resistance Role Runaway Running Series Side Signal Pathway Specificity Structure Survival Rate TP53 gene Techniques Testing Therapeutic Transactivation Transplantation Treatment Efficacy Tumor Cell Line Tumor Suppressor Proteins Uterine Cancer X-Ray Crystallography anti-cancer anti-cancer therapeutic antibody conjugate base cancer cell cancer therapy cell injury chemotherapy design drug discovery genotoxicity improved in vivo inhibitor/antagonist innovation leukemia leukemia treatment malignant breast neoplasm malignant stomach neoplasm molecular targeted therapies nanomolar neoplastic cell new therapeutic target novel novel therapeutics overexpression peptide L peptide drug prevent protein protein interaction rare cancer research and development response transcription factor trend tumor tumor growth tumorigenesis ubiquitin-protein ligase uptake weapons

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项目摘要

Despite an exponential increase over decades in research and development (R&D) expenditures by the pharmaceutical industry, the average number of new drugs approved annually by the FDA, 25 or so, has remained stagnant. The unsustainable trend of runaway spending in R&D directly contributes to skyrocketing health care costs across the country, underscoring an urgent need for new drug targets and classes. Protein-protein interactions (PPIs) control all aspects of cellular processes and are considered to be the “Holy Grail” in drug discovery and ultimate drug targets for disease intervention. Unfortunately, neither of the two major classes of existing drugs – low molecular weight compounds and antibodies are effective in interfering with intracellular PPIs. On the other hand, although small peptides are capable of effectively disrupting PPIs, they generally lack drug-like properties due primarily to their susceptibility to proteolytic degradation in vivo. A sensible solution to this long-running enigma in drug discovery is side chain-stapled L-peptides and proteolysis-resistant D-peptides. Antagonizing MDM2/MDMX to activate p53 is one of the most promising therapeutic paradigms for anticancer therapy. We have recently developed a series of high-affinity L- and D-peptide antagonists of MDM2 that effectively suppress tumor growth in vitro and in vivo in a p53- and MDM2-dependent manner. To achieve sustained and robust p53 activation and optimal therapeutic efficacy, however, dual-specificity antagonists of both MDM2 and MDMX are needed. The overall goal of this proposed research is to develop ultrahigh- affinity, dual-specificity, and proteolysis-resistant peptide antagonists of MDM2 and MDMX as a powerful p53- activating modality for the treatment of acute myeloid leukemia – where mutations of the TP53 gene are rare and MDM2 and MDMX are often amplified or over-expressed. This project may lead to the addition of new weapons to the existing anticancer arsenal and broadly impact the development of peptide therapeutics for targeted molecular therapy of many other diseases as well.

尽管在研究和开发（R＆D）支出数十年中，药品的指数增长了指数增长行业是FDA每年批准的新药的平均数量，大约25岁，一直停滞不前。这研发中失控支出的不可持续趋势直接导致整个人的医疗保健费用飞涨国家，强调迫切需要新药物目标和班级。蛋白质 - 蛋白质相互作用（PPI）控制所有细胞过程的各个方面，被认为是药物发现和最终药物靶标的“圣杯” 疾病干预。不幸的是，两种主要类别的现有药物 - 低分子量化合物抗体可有效干扰细胞内PPI。另一方面，尽管小肽能够在有效破坏PPI的情况下，由于其对蛋白水解的敏感性，它们通常缺乏类似药物的特性体内降解。对药物发现中这种长期运行的谜的敏感解决方案是侧链塞L肽和抗蛋白水解的D肽。对抗MDM2/MDMX激活p53是最有前途的用于抗癌治疗的治疗范例。我们最近开发了一系列高亲和力L-和D肽 MDM2的拮抗剂可有效抑制体外和体内p53-和MDM2依赖性的肿瘤生长方式。但是，为了实现持续且强大的p53激活和最佳治疗，双特异性需要MDM2和MDMX的拮抗剂。这项拟议研究的总体目标是发展超高 - MDM2和MDMX的亲和力，双特异性和抗蛋白水解肽拮抗剂作为强大的P53-- 激活急性髓样白血病的方法 - TP53基因的突变很少见，MDM2 MDMX通常会放大或过表达。该项目可能会导致在现有的抗癌武器库，并广泛影响肽治疗的发展，以靶向分子疗法其他疾病也是如此。