New insights into FOX proteins in cancer.

Abstract

Forkhead box (FOX) proteins are transcription factors whose dysregulation drives tumor initiation, metastasis, and therapy resistance, yet their direction of effect is determined by cellular context rather than by their conserved DNA-binding domain. Applying explicit criteria across all 44 human members, we find context-dependence to be the modal behavior, reversing in some cases within a single indication. This creates an inversion for drug discovery: The one structurally tractable region is common to the whole family, whereas the regions conferring selectivity are the least characterized. We assess small-molecule inhibition, covalent ligand discovery, targeted degradation and indirect pathway modulation against the evidence for direct target engagement and identify nonconserved regulatory surfaces as the more promising route to selective FOX-directed agents.