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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA170741-03
Application #
8677828
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Qian, Ziqing; LaRochelle, Jonathan R; Jiang, Bisheng et al. (2014) Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery. Biochemistry 53:4034-46