? PROJECT 1 Transcription factor (TF) deregulation underlies numerous diseases including cancer; however, the selective targeting of TFs with small molecule probes/leads remains elusive. Our research program seeks to exploit the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for TF probe/lead modulator discovery. Specifically, we seek to develop novel and efficient reaction methods to rapidly construct diverse Au-based pharmacophore libraries and to leverage these unique compound sets, and a streamlined screening strategy, to discover selective modulators of the model oncogenic transcription factor c- MYC. This study will develop a generalizable platform to target ?undruggable? targets such as protein-protein interfaces or TFs, using ?caged? gold centers via two ways: i) directly ligate gold to specific amino acids, or ii) covalently modify specific amino acids by transfer of coordinated ligands via reductive elimination in a manner similar to chemistry performed by transition metal-based catalysts. The studies will extend the breadth of stable gold ligands through optimization of Au catalytic processes, advance our understanding of the tunable reactivity and bioorthogonality of Au-based pharmacophores and potentially set the stage for a generalized strategy to target ?undruggable? proteins. A primary innovation of the proposed studies is the potential to dramatically alter, via covalent modification, protein surface structure/electronics and thereby influence function. CPRI mentorship and research support cores will further facilitate this project in a number of key ways. Specifically, the Computational Core will assist in the development of new predictive structure-activity relationship (SAR) models for Au-based probes and computational c-MYC/MAX-ligand structural models to guide probe design; the Translational Core will facilitate assay development, validation, and implementation (and eventually first in animal assessments including PK and ADMET); and the COBRE for Molecular Medicine?s Organic Synthesis Core will strategically support ligand synthesis/scale-up. This will also be augmented by a COBRE mentorship team with extensive expertise in transcription factor lead discovery, cancer biology, and pharmaceutical science.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM130456-01A1
Application #
9854238
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2020-03-01
Project End
2025-01-31
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526