# Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery

> **NIH NIH P20** · UNIVERSITY OF KENTUCKY · 2020 · $289,375

## Abstract

PROJECT SUMMARY/ABSTRACT – 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.

## Key facts

- **NIH application ID:** 9854238
- **Project number:** 1P20GM130456-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Samuel Gorman Awuah
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $289,375
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854238

## Citation

> US National Institutes of Health, RePORTER application 9854238, Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery (1P20GM130456-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9854238. Licensed CC0.

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