CGK 733

CGK733 is a potent ATM/ATR inhibitor, used for the research of cancer.

Signaling Pathways >> Cell Cycle/DNA Damage >> ATM/ATR

Signaling Pathways >> PI3K/Akt/mTOR >> ATM/ATR

Research Areas >> Cancer

ATM

ATR

CGK733 (4.2 ng/μL-12.5 ng/μL) enhances taxol-induced cytotoxicity in HBV-positive HCC cells. CGK733 (4.2 ng/μL) accelerates the formation of multinucleated cells and promotes the exit of mitosis in taxol-treated HBV-positive HCC cells[1]. CGK733 (10 μM) causes the loss of cyclin D1 through the ubiquitin-dependent proteasomal degradation pathway in MCF-7 and T47D breast cancer cell lines. CGK733 (0.6-40 μM) shows inhibitory activities against proliferation of LnCap prostate cancer cells, HCT116 colon cancer cells, MCF-7 and T47D estrogen receptor positive breast cancer cells, and MDA-MB436 ER negative breast cancer cells. Moreover, CGK733 inhibits proliferation of non-transformed mouse BALB/c 3T3 embryonic fibroblast cells. In addition, CGK733 (10 μM) inhibits MCF-7 proliferation, and the effect can not be suppressed by pan-caspase inhibition[2]. CGK733 (10 μM) results in 1.6-fold increase in ATM reporter activity in HEK-293 cells[3].

CGK733 (25 mg/kg, i.p.) increases the ATM reporter activity (reports inactivation of ATM kinase activity) compared to control mice, with 2.4-fold, 3.1-fold, and 1.3-fold changes at 1, 4, and 8 hours, respectively[3].

Cells are seeded in 96-well plates at a predetermined optimal cell density to ensure exponential growth for duration of the assay. After a 24 h preincubation, growth medium is replaced with experimental medium containing the appropriate drug concentrations or 0.1% (v/v) vehicle control. After a 48 h incubation, cell proliferation is estimated using the sulforhodamine B colorimetric assay and expressed as the mean ± SE for six replicates as a percentage of vehicle control (taken as 100%). Experiments are performed independently at least three times. Statistical analyses are performed using a two-tailed Student's t test. P < 0.05 is considered to be statistically significant[2].

Four to six weeks old athymic CD-1 female mice are acclimatized for at least one week before use. The mice are injected sub-cutaneously with 2×106 D54-ATMR cells in each flank. Tumors are allowed to grow to the size of 100-150 mm3. Mice are injected intraperitoneally with vehicle control (DMSO), CGK-733, KU-55933 (25 mg/kg) or irradiated with 5 Gy to each flank. Bioluminescence is acquired on Xenogen IVIS Spectrum system after injecting 400 μg/100 μL of D-luciferin at baseline (-3h) as well as 1, 4, and 8 hours after drug administration[3].

[1]. Wang H, et al. CGK733 enhances multinucleated cell formation and cytotoxicity induced by taxol in Chk1-deficient HBV-positive hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2012 May 25;422(1):103-8.

[2]. Alao JP, et al. The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation. Radiat Oncol. 2009 Nov 10;4:51.

[3]. Williams TM, et al. Molecular imaging of the ATM kinase activity. Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):969-77.

Wortmannin | Ceralasertib(AZD6738) | Berzosertib (VE-822) | KU55933 (ATM Kinase Inhibitor) | VE-821 | AZD-0156 | KU 60019 | AZ20 | AZD1390 | CP-466722 | ETP-46464 | KU 59403