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A novel pyrazolopyrimidine ligand of human PGK1 and stress sensor DJ1 modulates the shelterin complex and telomere length regulation
DOI:
10.1016/j.neo.2019.07.008
Authors:
Alan E.
Bilsland
(University of Glasgow)
,
Yu
Liu
(University of Glasgow)
,
Andrew
Turnbull
(Cancer Research Technology Ltd)
,
David
Sumpton
(Cancer Research UK Beatson Institute)
,
Katrina
Stevenson
(University of Glasgow)
,
Claire J.
Cairney
(University of Glasgow)
,
Susan M.
Boyd
(CompChem Solutions Ltd)
,
Jon
Roffey
(Cancer Research Technology Ltd)
,
David
Jenkinson
(Cancer Research Technology Ltd)
,
W. Nicol
Keith
(University of Glasgow)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Neoplasia
, VOL 21
, PAGES 893 - 907
State:
Published (Approved)
Published:
September 2019

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.
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I04-Macromolecular Crystallography
Added On:
28/08/2019 15:27
Documents:
zz5n5n.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)