Abstract
Telomere dysfunction is a hallmark of cell aging and defects in
telomere maintenance give rise to several “telomeropathies” associated with
accelerated aging and cancer predisposition, such as dyskeratosis congenita
(1,2). Several agents
have been identified which increase telomerase levels in aging cells and these
are being investigated for effects in models of stress/aging (3). Signal
transduction pathways exist in cancer cells which regulate cell immortality and
gene expression and proof of concept studies have demonstrated the concept for
using telomerase promoter assays to identify regulators of telomere signalling
(4). A cell-based reporter gene assay of hTERT promoter activity was used to
screen a kinase focused library leading to the identification of CRT0063465,
which inhibits hTERT promoter activity in the low nM range. Photoaffinity
labelling identified the key glycolytic kinase, PGK1, and oxidative stress
response regulator, DJ1, as the cellular targets of CRT0063465, with binding
confirmed using X-ray crystallography and SPR.
In silico molecular modelling suggests that PGK1 and DJ1 form a
complex
in vivo, creating an interfacial binding
site for CRT0063465. Both targets are shown here to be novel telomere binding
proteins and compound treatment affects this activity, in addition to causing
altered composition of the core telomere-protective shelterin complex.
CRT0063465 has telomere- and cyto-protective effects, promising PK in mice, and
is active in cells at low nM concentration. Hence, CRT0063465 represents a new
telomere-protective agent with a mechanism of action distinct from other agents
in this space and potential for use in chemoprevention settings (4).
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A novel telomerase activator
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4.
Bilsland, A.E., Hoare, S., Stevenson, K., Plumb, J., Gomez-Roman, N., Cairney,
C., Burns, S., Lafferty-Whyte, K., Roffey, J., Hammonds, T., et al. (2009).
Dynamic telomerase gene suppression via network effects of GSK3
inhibition.
PloS one 4 e6459
5.
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).
Neoplasia 21 893–907
