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"""""""".

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-SRLB-9 (M1))
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Fu, Yali
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Taatjes, Dylan J (2017) Transcription Factor-Mediator Interfaces: Multiple and Multi-Valent. J Mol Biol 429:2996-2998
Poss, Zachary C; Ebmeier, Christopher C; Odell, Aaron T et al. (2016) Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics. Cell Rep 15:436-50
Allen, Benjamin L; Taatjes, Dylan J (2015) The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol 16:155-66
Pelish, Henry E; Liau, Brian B; Nitulescu, Ioana I et al. (2015) Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526:273-276
LaRochelle, Jonathan R; Cobb, Garrett B; Steinauer, Angela et al. (2015) Fluorescence correlation spectroscopy reveals highly efficient cytosolic delivery of certain penta-arg proteins and stapled peptides. J Am Chem Soc 137:2536-2541
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
Poss, Zachary C; Ebmeier, Christopher C; Taatjes, Dylan J (2013) The Mediator complex and transcription regulation. Crit Rev Biochem Mol Biol 48:575-608
Holub, Justin M; Larochelle, Jonathan R; Appelbaum, Jacob S et al. (2013) Improved assays for determining the cytosolic access of peptides, proteins, and their mimetics. Biochemistry 52:9036-46
Phillips, Andrew J; Taatjes, Dylan J (2013) Small molecule probes to target the human Mediator complex. Isr J Chem 53:588-595