CG0009 [2-{4-[(2-diethylamino-ethyl)-methyl-amino]-phenyl}-3H-imidazo[4,5-b]pyridine-7-carboxylic
acid(4-methyl-pyridin-3-yl)-amide] is a novel Glycogen Synthase Kinase 3
(GSK3) inhibitor. CG0009, a derivative of imidazopyridine carboxamide, was
identified during extensive lead optimization of hits for inhibitors of GSK3
[1].
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| CG0009: 2D and 3D Structure |
GSK3 Inhibitors as Anti-Cancer Agents
Glycogen
synthase kinase 3 (GSK3) is a serine/threonine kinase expressed as two similar
isoforms, α and β. GSK3 was initially identified as a metabolic regulator that
phosphorylates and inhibits glycogen synthase. GSK3 is a constitutively active
enzyme in normal cells and undergoes rapid inhibition by stimuli. Activity of
GSK3 is increased upon phosphorylation at Tyr216, whereas phosphorylation at
Ser21 in GSK3α and Ser9 in GSK3β inhibits GSK3 activity. GSK3 is a key
suppressor of the canonical Wnt signaling pathway of adenomatous polyposis coli
(APC), axin and β-catenin, which is involved in embryonic cell fate determination
and cell renewal. GSK3β phosphorylates β-catenin, which leads to its
destruction, thus suppressing signals that otherwise promote cell
proliferation. GSK3β inhibitors have been identified as therapeutic targets in
Alzheimer’s disease, neurodegenerative disorders and bipolar disorder. Recent
studies have additionally shown that GSK3β inhibitors induce growth suppression
and apoptosis in human chronic lymphocytic leukemia, glioma, colon cancer and
renal cell carcinoma. Although GSK3β-promoted oncogenesis is a paradoxical
issue, compelling evidence suggests that GSK3 is a target gene in malignancy.
CG0009 as Kinase Inhibitor
CG0009,
inhibits proliferation, induces apoptosis cell death, and activates the p53-Bax
pathway in breast cancer cells, predominantly via cyclin D1 depletion. CG0009
induces significant growth inhibition and cell death in breast cancer cell
lines, with a wide range of IC50 values (between 0.49
(MCF7) and 11 µM (NCI/ADR-RES and BT549)), whereas other GSK3 inhibitors
(namely, LiCl, SB216763 and kenpaullone) have little effect on cell
growth at concentrations up to 100 µM, which is much higher than that normally
used for in vitro experiments, except LiCl (used at 10 ~
20 mM) [2].
CG0009 induced complete depletion of cyclin D1 in sensitive breast cancer cells.
The sensitivity to CG0009 and the time required for complete depletion of
cyclin D1 is correlated. Most CG0009-hypersensitive MCF7 cells showed cyclin D1
depletion at 16 h, while the CG0009-moderately sensitive cell lines, HS578T,
MAD-MB-435, and MDA-MB-231, exhibited depletion at 40 h following CG0009
treatment. These findings are inconsistent with previous data showing that
phosphorylation of cyclin D1 at Thr286 by GSK3β enhances nuclear export
and degradation. Although cyclin D1 depletion by CG0009 may occur partly as a
result of the decrease in ERα protein in MCF7 cells, it is proposed that
this cyclin D1 decrease is a major cause of CG009-induced breast cancer cell
death. Additionally, T47D cells expressed about 10-fold higher cyclin D1
transcripts, compared with the MCF7 cell line. Accordingly, researchers
conclude that CG0009 is an effective therapeutic agent for breast cancer,
regardless of functional ER status, and cyclin D1 overexpression is an
unfavorable response marker for the agent [2].
References:
1. Cho,
J. -M.; et. al. Imidazopyridine derivatives inhibiting
protein kinase activity, method for the preparation thereof and pharmaceutical
composition containing same. WO2007083978A1
2. Kim,
H. M.; et. al. CG0009, a novel glycogen synthase
kinase 3 inhibitor, induces cell death through cyclin D1 depletion in breast
cancer cells. PLoS One 2013, 8(4), e60383. (free copy)
