The ataxia telangiectasia mutated (ATM) and ATM-related (ATR) kinases facilitate the resistance of cancer cells to genotoxic agents. CGK733 is a thiourea-containing compound that inhibits both ATM and ATR with IC50 values of ~200nM. Treatment of MCF-7 breast cancer cells with 10μM CGK733 reduced the expression of cyclin D1 within 2h of exposure. CGK733 at 5-20μM induced a loss of cyclin D1 protein in T47D cells. In MCF-7 cells, treatment with CGK733 at 10μM for 24h reduced the expression of both phosphorylated and total retinoblastoma tumor suppressor protein. CGK733 at a dosage of 10μM inhibited the proliferation of MCF-7, T47D, HCT116, BALB/c3T3, MDA-MB436, and LnCap cancer cells.[3] In mice inoculated with D54-ATMR cells, treatment with CGK733 (25mg/kg) for 1, 4, and 8h induced an increase in ATM reporter activity with 2.4-fold, 3.1-fold, and 1.3-fold changes, respectively, over the control group.[4]
作用机制
CGK733 is a small-molecule inhibitor of both ATM and ATR.[3]
CGK733 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BALB/c 3T3 mouse embryonic fibroblasts
2.5-20 μM
48 h
Inhibited cell proliferation
Radiat Oncol. 2009 Nov 10;4:51.
HCT116 colon cancer cells
2.5-20 μM
48 h
Inhibited cell proliferation
Radiat Oncol. 2009 Nov 10;4:51.
Bone marrow-derived macrophages (BMMs)
1-6 μM
96 h
Evaluate cytotoxicity, apoptosis, and inhibitory effects of CGK733 on osteoclast differentiation. Results showed CGK733 had no cytotoxicity at 1-6 μM, did not induce apoptosis, and dose-dependently inhibited RANKL-induced osteoclast differentiation, with optimal effect at 6 μM.
iScience. 2023 Aug 29;26(10):107760.
LNCaP prostate cancer cells
10 μM
6 h
Induced decline in cyclin D1 protein levels via ubiquitin-26S proteasome pathway
Radiat Oncol. 2009 Nov 10;4:51.
T47D breast cancer cells
5-20 μM
6 h
Induced decline in cyclin D1 protein levels via ubiquitin-26S proteasome pathway
Radiat Oncol. 2009 Nov 10;4:51.
MCF-7 breast cancer cells
10 μM
2-6 h
Induced decline in cyclin D1 protein levels via ubiquitin-26S proteasome pathway
Radiat Oncol. 2009 Nov 10;4:51.
CaSki cells
50 nM
24 h
Inhibited ATM activity, reversed HDAB-induced S phase arrest and promoted apoptosis
Sci Rep. 2015 Jun 4;5:10893.
HeLa cells
50 nM
24 h
Inhibited ATM activity, reversed HDAB-induced S phase arrest and promoted apoptosis
Sci Rep. 2015 Jun 4;5:10893.
CGK733 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J female mice
Ovariectomy (OVX)-induced osteoporosis model
Intraperitoneal injection
3 mg/kg or 6 mg/kg
Every other day for 6 weeks
Evaluate therapeutic effects of CGK733 on OVX-induced bone loss. Results showed CGK733 (especially 6 mg/kg) significantly ameliorated OVX-induced bone microstructure deterioration, reduced osteoclast numbers, increased trabecular bone volume/tissue volume (BV/TV), trabecular number (Tb.N) and thickness (Tb.Th), decreased trabecular separation (Tb.Sp), and showed no toxicity to heart, liver, or kidney.
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