A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.

Autor:	Bilsland AE; Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1QH, UK., Liu Y; Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1QH, UK., Turnbull A; Cancer Research Technology Ltd., Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, UK., Sumpton D; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK., Stevenson K; Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1QH, UK., Cairney CJ; Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1QH, UK., Boyd SM; CompChem Solutions Ltd, St John's Innovation Centre, Cambridge, CB4 0WS, UK., Roffey J; Cancer Research Technology Ltd., Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, UK., Jenkinson D; Cancer Research Technology Ltd., Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, UK., Keith WN; Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1QH, UK. Electronic address: nicol.keith@glasgow.ac.uk.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2019 Sep; Vol. 21 (9), pp. 893-907. Date of Electronic Publication: 2019 Aug 08.
DOI:	10.1016/j.neo.2019.07.008
Abstrakt:	Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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