? 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.