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)