Accessing the druggable genetic programmes governed by mammalian bHLH-PAS transcription factors

Cells, tissues and organs use sensory communication networks dependent on a variety of small molecules and proteins that selectively recognise them. This form of signalling is typically reliant on the metabolic state inside the cell, or changes in the extracellular environment, both of which can alter the levels of small-molecule signals. The binding proteins must form adaptive physiological responses to meet those signals.

We will explore a family of human gene regulating proteins, known as the bHLH-PAS transcription factors, whose 3D structure allows binding to small molecules and to genomic sites for controlling gene expression. We will find the cellular small molecules and synthetic drug-like compounds that can bind and modulate the activities of these proteins.

Understanding how such signalling molecules interact with bHLH-PAS transcription factors should inform future drug development for a variety of unmet human conditions including cancer.