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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
New insights into FOX proteins in cancer
Sara Alrawashdeh1, Gazia Buzaakuk1, Raghd Obidat1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
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.
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