SUPR Peptides to Inhibit Undruggable Cancer Target (PQ18)

SUPR 肽抑制无法药物治疗的癌症靶标 (PQ18)

基本信息

批准号：
8874750
负责人：
RICHARD W ROBERTS
金额：
$ 44.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2012-09-17 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874750
关键词：
Address Affinity Amino Acids Antibodies Antineoplastic Agents Antitumor Response Applications Grants Binding Biological Biological Availability C-terminal Cell Culture Techniques Cell Membrane Permeability Cellular Membrane Characteristics Chemicals Cyclic Peptides Development Dose Drug resistance Enzymes Exhibits Genes Genetic Code Goals Guanosine Triphosphate Human Immune response Immunosuppression KRAS2 gene Libraries Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Membrane Membrane Proteins Messenger RNA Modification Mus Mutate N Domain Nucleotides Oncogenic Oral Peptide Hydrolases Peptides Pharmaceutical Preparations Phenotype Play Property Proteins Reagent Resistance Role Route Scanning Serum Solutions Specificity Stat3 protein Testing Therapeutic Time base cancer cell cancer immunotherapy cancer therapy cell growth design drug candidate drug discovery improved in vivo insight mouse model new technology novel nucleotide analog originality outcome forecast pre-clinical protein aminoacid sequence protein farnesyltransferase protein protein interaction public health priorities ras Proteins response src Homology Region 2 Domain therapeutic target tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): This application aims to demonstrate that Scanning Unnatural Protease Resistant (SUPR) peptides provide a general solution to the problem of targeting traditionally undruggable proteins. To do this, we will use mRNA display with an expanded genetic code to create a new class highly stabilized, membrane-permeant peptides that can block or modulate protein-protein interactions for two of the most important intracellular proteins conferring the oncogenic phenotype-the activated form of Ras and the Stat3 protein. Our three Specific Aims are: 1) To design stabilized SUPR peptides targeting intracellular "undruggable" proteins involved in cancer transformation or maintenance, 2) To characterize and enhance selected SUPR peptide functions towards cancer drug applications, and 3) To evaluate in vivo characteristics and assess the therapeutic potential of optimized SUPR peptide drug candidates for cancer treatment in mice. Overall, this project is intended to develop novel molecules as well as a general approach to target cancer-relevant proteins that have proved challenging up to this point-so much so that the proteins may be called "undruggable."

描述（由申请人提供）：本申请旨在证明扫描非天然蛋白酶抗性（SUPR）肽为靶向传统上不可成药的蛋白质的问题提供了通用解决方案。为此，我们将使用具有扩展遗传密码的 mRNA 展示来创建一类新的高度稳定的膜渗透肽，它可以阻断或调节细胞内两种最重要的蛋白质-蛋白质相互作用。赋予致癌表型的蛋白质——Ras 和 Stat3 蛋白质的激活形式。我们的三个具体目标是：1) 设计针对参与癌症转化或维持的细胞内“不可成药”蛋白质的稳定 SUPR 肽，2) 表征和增强选定的 SUPR 肽功能以实现癌症药物应用，以及 3) 评估体内特性和评估优化的 SUPR 肽候选药物用于小鼠癌症治疗的治疗潜力。总体而言，该项目旨在开发新型分子以及针对癌症相关蛋白质的通用方法，到目前为止，这些蛋白质已被证明具有挑战性，以至于这些蛋白质可以被称为“不可成药”。