Directing the Mediator Complex: Bivalent approaches to Reconstituting or Inhibiti

描述（由申请人提供）：该项目结合了三位不同研究人员的专业知识，共同努力解决NCI挑衅问题#18：“是否有新技术来抑制传统上‘不可药物’的靶分子，如致癌表型所需的转录因子？”为了解决这个问题，我们将开发三种不同但协同的化学物质，以提供干扰转录因子等不可药物靶点的新分子。同时，我们将评估它们对细胞内目标的访问，并定义细胞访问编码的结构特征。这些概念将在p53转录因子（一种典型的抗癌靶点）及其对中介复合物MED17亚基的影响的背景下发展。

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".