Dataset Information

Identification of novel pyrazolopyrimidine compounds that modulate the shelterin complex and telomere length regulation via phosphoglycerate kinase 1 and stress sensor DJ1

ABSTRACT: Telomere signalling and metabolic dysfunction are hallmarks of cell aging, and are associated with a variety of pathologies. Identification of new agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. Here we report identification and characterization of a pyrazolopyrimidine compound series that emerged from screens focused on cell immortality pathways and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We initially performed structure-activity studies on the series to develop an analogue suitable for use as a photoaffinity probe to deconvolute the cellular targets. Biophysical and structural analyses confirmed these targets, pointing to the possibility that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress have previously been linked to telomere signalling and exemplar compound CRT0063465 was found to block hypoglycaemic telomere shortening. Intriguingly, we find that both PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment not only modulates these interactions but also affects composition of the Shelterin complex, in addition to conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results highlight the power of chemical approaches in discovery of novel biological mechanisms and demonstrate therapeutic potential of the compound series.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Diploid Cell

DISEASE(S): Colon Cancer

SUBMITTER: David Sumpton

LAB HEAD: Nicol Keith

PROVIDER: PXD011356 | Pride | 2019-07-19

REPOSITORIES: Pride

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			Action	DRS
	120115_DAS_OT_ALB_M02_191214_PC.msm (F012279).mzid_120115_DAS_OT_ALB_M02_191214_PC.msm_(F012279).pride.mgf.gz	Mzid
	120115_DAS_OT_ALB_M02_191214_PC.msm (F012279).pride.mztab.gz	Mztab
	120115_DAS_OT_ALB_M02_191214_PC.msmF012279.mzid.gz	Mzid
	120115_DAS_OT_ALB_M02_191214_PC.msmF012279.mzid_120115_DAS_OT_ALB_M02_191214_PC.msm_F012279.MGF	Mzid
	120115_DAS_OT_ALB_M02_191214_PC.raw	Raw

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Publications

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

Bilsland Alan E AE Liu Yu Y Turnbull Andrew A Sumpton David D Stevenson Katrina K Cairney Claire J CJ Boyd Susan M SM Roffey Jon J Jenkinson David D Keith W Nicol WN

Neoplasia (New York, N.Y.) 20190808 9

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 ...[more]

PMID: 31401411

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