Thursday, September 24, 2015

Drugs in Clinical Pipeline: CG0009 I Kinase Inhibitor | GSK3 Inhibitor

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].

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].
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)