Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors

Sixteen human proteins that control which genes are switched on or off share a common structure that makes them promising targets for new drugs. These proteins, called bHLH-PAS transcription factors, are each linked to different diseases—cancers, metabolic disorders, inflammatory conditions, and psychiatric illnesses—and they do not compensate for one another if one fails. Despite their therapeutic potential, researchers lack chemical tools to precisely control them. This project aims to find small molecules that bind to each protein, map the genes and cellular pathways each one regulates, and understand how those chemical ligands alter the proteins’ activity. If successful, the work will transform these proteins from structurally understood but functionally opaque targets into druggable switches. That could open the door to developing drugs that correct gene expression in specific diseases without affecting related family members. The research is fundamental science: it will first establish the basic rules of how these proteins respond to chemical signals. Similar fundamental work on other transcription factor families has led to cancer therapies and treatments for metabolic disease. A deeper understanding of bHLH-PAS biology could eventually yield precision medicines for conditions that currently lack targeted treatments.