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抗蛋白酶(SUPR)多肽提供了一种针对传统上不可药物的蛋白质的一般解决方案。为了做到这一点，我们将使用带有扩展遗传密码的mrna展示来创建一类高度稳定的膜透过性多肽，它可以阻断或调节两个最重要的细胞内蛋白质之间的相互作用。 与致癌表型相关的蛋白质--RAS的激活形式和STAT3蛋白。我们的三个具体目标是：1)设计稳定的针对参与癌症转化或维持的细胞内“不可药物”蛋白的SUPR多肽，2)表征和增强选定的SUR多肽用于癌症药物应用的功能，以及3)评估优化的SUR多肽候选药物在体内的特性和评估用于小鼠癌症治疗的优化的SUPR多肽候选药物的治疗潜力。总体而言，该项目旨在开发新的分子以及一种针对癌症相关蛋白的通用方法，到目前为止，这些蛋白已被证明具有挑战性-以至于这些蛋白可能被称为“无法下药”。 公共卫生相关性：开发新技术以抑制无法用药治疗的癌症靶点是重要的公共卫生优先事项。它可以扩大我们发现新抗癌药物的能力，并提高我们管理癌症的能力。成功完成拟议的研究不仅将为癌症提供许多新的治疗机会，还将为癌症药物的发现提供新的工具。

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.