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Anticancer peptide therapeutics

抗癌肽疗法

基本信息

批准号：
9994738
负责人：
Yin Wang
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 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9994738
关键词：
Acute Myelocytic Leukemia Affinity Antibodies Antineoplastic Agents Apoptotic Binding Cancer Patient Cancerous Cell physiology 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 Normal Cell Pathway interactions Patients Peptide Hydrolases Peptide antibodies Peptides Pharmaceutical Preparations Pharmacology Play Pluripotent Stem Cells Predisposition Primary Neoplasm Property 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 acute myeloid leukemia cell 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 relapse leukemia treatment malignant breast neoplasm malignant stomach neoplasm molecular targeted therapies myeloid leukemia cell 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

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.

尽管几十年来制药公司的研究和开发（R&D）支出呈指数级增长，在制药行业，FDA每年批准的新药平均数量为25种左右，一直停滞不前。的研发支出失控的不可持续趋势直接导致了全球医疗保健成本的飙升，国家，强调迫切需要新的药物目标和类别。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点的“圣杯”，疾病干预。不幸的是，现有的两大类药物--低分子量化合物并且抗体可有效干扰细胞内PPI。另一方面，虽然小肽能够由于它们对蛋白水解的敏感性，体内降解。对于这个药物发现中的长期谜团，一个明智的解决方案是侧链装订的L-肽和抗蛋白水解的D-肽。拮抗MDM 2/MDMX以激活p53是最有前途的方法之一。抗癌治疗的治疗范例。我们最近开发了一系列高亲和力的L-和D-肽在体外和体内以p53-和MDM 2-依赖的方式有效抑制肿瘤生长的MDM 2拮抗剂，方式然而，为了实现持续和稳健的p53激活和最佳治疗功效，双重特异性需要MDM 2和MDMX两者的拮抗剂。这项研究的总体目标是开发一种新的... MDM 2和MDMX的亲和性、双特异性和蛋白水解抗性肽拮抗剂作为一种强大的p53- 治疗急性髓性白血病的激活方式-其中TP 53基因突变罕见，MDM 2 和MDMX经常被放大或过度表达。这一项目可能导致在现有的基础上增加新武器抗癌武器库和广泛影响肽治疗的发展，为靶向分子治疗的许多其他疾病也是如此。