SUPR Peptides to Inhibit Undruggable Cancer Target (PQ18)

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用药的蛋白质的问题提供了一种通用解决方案。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，其可以阻断或调节两种最重要的细胞内蛋白质-蛋白质相互作用。 赋予致癌表型的蛋白-Ras和Stat 3蛋白的活化形式。我们的三个具体目标是：1）设计靶向参与癌症转化或维持的细胞内“不可用药的”蛋白质的稳定化SUPR肽，2）表征和增强所选SUPR肽对癌症药物应用的功能，和3）评估优化的SUPR肽药物候选物用于小鼠癌症治疗的体内特征和治疗潜力。总的来说，该项目旨在开发新的分子以及一种靶向癌症相关蛋白质的通用方法，这些蛋白质到目前为止已被证明具有挑战性，以至于这些蛋白质可能被称为“不可药用的”。" 公共卫生相关性：开发新技术以抑制不可治疗的癌症靶点是一项重要的公共卫生优先事项。它可以扩大我们发现新癌症药物的能力，提高我们管理癌症的能力。这些研究的成功完成不仅将为癌症提供许多新的治疗机会，还将为癌症药物发现提供新的工具。

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." PUBLIC HEALTH RELEVANCE: The development of novel technologies to inhibit undruggable therapeutic cancer targets is an important public health priority. It can expand our abilities to discover new cancer drugs and improve our abilities to manage cancer. Successful completion of the proposed studies will not only offer many new treatment opportunities for cancer, but also provide new tools for cancer drug discovery.