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Updated: May 11, 2026

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
Broadly applicable methodology for the rapid and dosable small molecule-mediated regulation of transcription factors
Matthew D Shoulders1, Lisa M Ryno, Christina B Cooley
1Department of Chemistry, §Department of Molecular and Experimental Medicine, ∥The Skaggs Institute of Chemical Biology, and ⊥Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
Abstract:
Direct and selective small molecule control of transcription factor activity is an appealing avenue for elucidating the cell biology mediated by transcriptional programs. However, pharmacologic tools to modulate transcription factor activity are scarce because transcription factors are not readily amenable to small molecule-mediated regulation. Moreover, existing genetic approaches to regulate transcription factors often lead to high nonphysiologic levels of transcriptional activation that significantly impair our ability to understand the functional implications of transcription factor activity. Herein, we demonstrate that small molecule-mediated conformational control of protein degradation is a generally applicable, chemical biological methodology to obtain small molecule-regulated transcription factors that modulate transcriptional responses at physiologic levels in human cells. Our establishment of this approach allows for the rapid development of genetically encoded, small molecule-regulated transcription factors to explore the biologic and therapeutic impact of physiologic levels of transcription factor activity in cells.
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