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Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer

DOI: 10.18632/oncotarget.11487 DOI Help

Authors: Judith E. Unterlass (Newcastle University) , Arnaud Basle (University of Newcastle Upon Tyne) , Timothy J. Blackburn (Newcastle University) , Julie Tucker (Newcastle University) , CĂ©line Cano (Newcastle University) , Martin E. M. Noble (Newcastle University) , Nicola J. Curtin (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Oncotarget

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 9948

Open Access Open Access

Abstract: 3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in PHGDH-amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH-amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected. As a first step towards design of a chemical probe for PHGDH, we report a fragment-based drug discovery approach for the identification of PHGDH inhibitors. We designed a truncated PHGDH construct that gave crystals which diffracted to high resolution, and could be used for fragment soaking. 15 fragments stabilising PHGDH were identified using a thermal shift assay and validated by X-ray crystallography and ITC competition experiments to exhibit 1.5-26.2 mM affinity for PHGDH. A structure-guided fragment growing approach was applied to the PHGDH binders from the initial screen, yielding greater understanding of the binding site and suggesting routes to achieve higher affinity NAD-competitive inhibitors.

Journal Keywords: cancer metabolism; PHGDH; serine metabolism; drug discovery; fragments

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Documents:
11487-173711-3-PB.pdf