c-Myc是一种常见的原癌基因，其异常表达是癌变过程中较早出现的分子变异，在肿瘤细胞转化、恶化、迁移等方面均扮演着重要角色，是目前研究最为广泛的癌基因之一。不同于传统的靶蛋白激酶，靶向非激酶类(如c-Myc转录因子)仍然是一个挑战。近年来，一种人工合成的蛋白靶向降解嵌合分子(PROTAC)能利用细胞固有的泛素-蛋白酶体系统调控靶点蛋白降解，已经成为开发靶向药物的新思路，并开始从基础走向临床。.本项目以c-Myc转录因子为靶点，借助高通量富集筛选技术筛选能够结合cMyc蛋白的多肽序列，并对其结合特异性进行分析；探索逆反构象对多肽药物稳定性以及生物活性的影响；利用PROTAC技术合成多肽嵌合分子，并在细胞水平上分析多肽嵌合体对靶点的降解作用；研究多肽嵌合体对肿瘤细胞生长、转移侵袭的变化，揭示多肽嵌合体干预肿瘤细胞增殖等功能的分子机理；利用裸鼠皮下异植瘤模型验证多肽嵌合体的抗肿瘤作用。

c-Myc plays a central role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. It has been demonstrated that MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Therefore, Myc is an attractive target for novel cancer therapies. .As a transcription factor, therapeutically targeting cMyc has remained a challenge. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system (UPS). By exploiting the UPS, a novel class of small-molecules, the PROTACs (Proteolysis Targeting Chimeric) molecules, was designed to induce ubiquitination and degradation of targeted proteins. The technology is rapidly emerging as an alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs..In this project, we hypothesize that dysregulation of Myc oncoprotein activates a pro-invasion program through transcriptional regulation of several important targets. We hope to therapeutically target this oncogenic pathway by the identification of small peptides specifically binding and degrading cMyc protein by employing the PROTACs technology, thus identifying drug leads for the development of peptidomimetics to therapeutically target human cancers. Specific targeting of tumor cells using high affinity and highly selective peptides conjugated to conventional chemotherapeutics enables the use of low doses, eliminating the toxic effects of chemotherapeutics.