New insights into FOX proteins in cancer.

Authors

Sara Alrawashdeh, Gazia Buzaakuk, Raghd Obidat, Adam R Karpf, Carlos A Velázquez-Martínez

Published in

Drug discovery today. Pages 104824. Oct 05, 2026. Epub Oct 05, 2026.

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.

PMID:
42833394
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.