Directing the Mediator Complex: Bivalent approaches to Reconstituting or Inhibiti

描述（由申请人提供）：该项目结合了三个不同研究者的专业知识，共同努力解决NCI挑衅性问题#18：“是否有新技术来抑制致癌表型所需的传统'不可药'靶分子，如转录因子？“为了解决这个问题，我们将开发三种不同的，但协同的化学物质，以提供新的分子，干扰不可药用的目标，如转录因子。我们将评估它们对细胞内目标的访问，并定义编码细胞访问的结构特征。这些概念将在典型抗癌靶点p53转录因子及其对介体复合物MED 17亚基的影响的背景下发展。 公共卫生相关性：转录因子是癌症治疗干预的一个非常有吸引力的靶标，然而它们是一组俗称为“不可用药”的分子的一部分。该项目将开发实现这类目标所需的各种新技术。最初的研究目标是p53肿瘤抑制因子，这是一种被称为“基因组守护者”的转录因子。

DESCRIPTION (provided by applicant): This project combines the expertise of three different investigators in an orchestrated effort to address the NCI Provocative Question #18: "Are there new technologies to inhibit traditionally 'undruggable' target molecules, such as transcription factors, that are required for the oncogenic phenotype?" To address this question, we will develop three distinct, but synergistic, chemistries to provide new molecules that perturb undruggable targets such as transcription factors. In concert, we will evaluate their access to targets within cells and define the structural features that code for cellular access. These concepts will be developed in the context of the p53 transcription factor, a quintessential anti-cancer target, and its effects on the MED17 subunit of the Mediator complex. PUBLIC HEALTH RELEVANCE: Transcription factors are an extremely attractive target for therapeutic intervention in cancer, however they are part of a group of molecules colloquially referred to as "undruggable". This project will develop the types of new technologies needed to reach targets of this type. The initial target for study is the p53 tumor suppressor, a transcriptin factor that known as the "guardian of the genome".