A novel pyrazolopyrimidine ligand of human PGK1 and stress sensor DJ1 modulates the shelterin complex and telomere length regulation

Bilsland, A. E. , Liu, Y., Turnbull, A., Sumpton, D., Stevenson, K., Cairney, C. J., Boyd, S. M., Roffey, J., Jenkinson, D. and Keith, W. N. (2019) A novel pyrazolopyrimidine ligand of human PGK1 and stress sensor DJ1 modulates the shelterin complex and telomere length regulation. Neoplasia, 21(9), pp. 893-907. (doi: 10.1016/j.neo.2019.07.008) (PMID:31401411) (PMCID:PMC6700475)

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Abstract

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.

Item Type:Articles
Additional Information:This work was supported by the Glasgow Experimental Cancer Medicine Centre (funded by Cancer Research UK and the Chief Scientist Office, Scotland), Cancer Research UK grants C2193/A15584, C301/A12962, C301/A14762 and C301/A6691.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sumpton, Mr David and Cairney, Dr Claire and Liu, Ms Yu and Bilsland, Dr Alan and Stevenson, Mrs Katrina and Keith, Professor Nicol
Authors: Bilsland, A. E., Liu, Y., Turnbull, A., Sumpton, D., Stevenson, K., Cairney, C. J., Boyd, S. M., Roffey, J., Jenkinson, D., and Keith, W. N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Neoplasia
Publisher:Elsevier
ISSN:1522-8002
ISSN (Online):1476-5586
Published Online:08 August 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Neoplasia 21(9):893-907
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
551312Senectus: Exploitation of a Cell Senescence Drug Discovery ProgramNicol KeithCancer Research UK (CRUK)C301/A12962RI CANCER SCIENCES
415274Telomerase therapeuticsNicol KeithCancer Research UK (CRUK)C301/A6691RI CANCER SCIENCES
580722Optimisation of telomerase expression repressorsNicol KeithCancer Research UK (CRUK)14762ICS - EXPERIMENTAL THERAPEUTICS
573448Experimental Cancer Medicine Centre (ECMC)Thomas EvansChief Scientist office (CSO)N/AICS - EXPERIMENTAL THERAPEUTICS