CGK733
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MedKoo CAT#: 406386

CAS#: 905973-89-9

Description: CGK733 is an ATM inhibitor and ATR inhibitor, which significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells. These results suggest that CGK733 could potentially reverse the taxol resistance in HBV-positive HCC cells and may suggest a novel strategy to treat HBV-infected HCC patients.


Chemical Structure

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CGK733
CAS# 905973-89-9

Theoretical Analysis

MedKoo Cat#: 406386
Name: CGK733
CAS#: 905973-89-9
Chemical Formula: C23H18Cl3FN4O3S
Exact Mass: 554.01492
Molecular Weight: 555.84
Elemental Analysis: C, 49.70; H, 3.26; Cl, 19.13; F, 3.42; N, 10.08; O, 8.64; S, 5.77

Price and Availability

Size Price Availability Quantity
100.0mg USD 950.0 2 Weeks
200.0mg USD 1650.0 2 Weeks
500.0mg USD 2450.0 2 Weeks
1.0g USD 3750.0 2 Weeks
2.0g USD 4950.0 2 Weeks
5.0g USD 7850.0 2 Weeks
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Synonym: CGK733; CGK-733; CGK 733.

IUPAC/Chemical Name: 2,2-diphenyl-N-(2,2,2-trichloro-1-(3-(4-fluoro-3-nitrophenyl)thioureido)ethyl)acetamide

InChi Key: HLCDNLNLQNYZTK-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H18Cl3FN4O3S/c24-23(25,26)21(30-22(35)28-16-11-12-17(27)18(13-16)31(33)34)29-20(32)19(14-7-3-1-4-8-14)15-9-5-2-6-10-15/h1-13,19,21H,(H,29,32)(H2,28,30,35)

SMILES Code: O=C(NC(NC(NC1=CC=C(F)C([N+]([O-])=O)=C1)=S)C(Cl)(Cl)Cl)C(C2=CC=CC=C2)C3=CC=CC=C3

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: CGK 733 is a potent and selective inhibitor of ATM/ATR with IC50 of ~200 nM.
In vitro activity: CGK733, a small molecule inhibitor reportedly targeting the kinase activities of ATM and ATR, significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells. These results suggest that CGK733 could potentially reverse the taxol resistance in HBV-positive HCC cells and may suggest a novel strategy to treat HBV-infected HCC patients. Reference: Biochem Biophys Res Commun. 2012 May 25;422(1):103-8. https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(12)00797-8
In vivo activity: In order to confirm the functionality of ATM reporter in vivo, D54-ATMR tumors were established in nude mice and treated with DMSO (control), CGK733 or KU-55933 (both 25 mg/kg) and monitored bioluminescence over time. We observed significant increases in reporter activation in a time-dependent fashion in response to both KU-55933 and CGK733 treatment (Fig. 6A, 6B). There was an immediate increase in reporter activation 1 hour after injection, which was sustained and maximal at 4 hours. However, KU-55933 was markedly more effective in inducing reporter activation compared to CGK733 given at the same dose and method of administration. With KU-55933 treatment, reporter activation increased 9.0-fold at 1 and 4 hours, before dropping down to 4.2-fold at 8 hours after injection. The differences were statistically significant at all time-points compared to vehicle treated mice. CGK733 also induced increases in reporter activity over control mice, with 2.4-fold, 3.1-fold, and 1.3-fold changes observed at 1, 4, and 8 hours, respectively. Although both the 1 hour and 4 hour treatment with CGK733 treatment were significantly different from control mice, the 8 hour values returned to near control levels. The observed persistent inhibition of ATM in-vivo compared to the in vitro data is likely due to the drug being injected in the peritoneum, which is slowly and continually absorbed into the bloodstream over hours, thus creating prolonged ATM inhibition in tumors. Reference: Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):969-77. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23726004/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Soluble in DMSO, not in water 100.0 179.91

Preparing Stock Solutions

The following data is based on the product molecular weight 555.84 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Wang H, Zuo B, Wang H, Ren L, Yang P, Zeng M, Duan D, Liu C, Li M. 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. doi: 10.1016/j.bbrc.2012.04.115. Epub 2012 Apr 30. PMID: 22564734. 2. Alao JP, Sunnerhagen P. The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation. Radiat Oncol. 2009 Nov 10;4:51. doi: 10.1186/1748-717X-4-51. PMID: 19903334; PMCID: PMC2777912.
In vivo protocol: 1. Williams TM, Nyati S, Ross BD, Rehemtulla A. Molecular imaging of the ATM kinase activity. Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):969-77. doi: 10.1016/j.ijrobp.2013.04.028. Epub 2013 May 29. PMID: 23726004; PMCID: PMC3710537.

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1: Jekimovs C, Bolderson E, Suraweera A, Adams M, O'Byrne KJ, Richard DJ. Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising. Front Oncol. 2014 Apr 22;4:86. doi: 10.3389/fonc.2014.00086. eCollection 2014. Review. PubMed PMID: 24795863; PubMed Central PMCID: PMC4001069.

2: Tang ML, Khan MK, Croxford JL, Tan KW, Angeli V, Gasser S. The DNA damage response induces antigen presenting cell-like functions in fibroblasts. Eur J Immunol. 2014 Apr;44(4):1108-18. doi: 10.1002/eji.201343781. Epub 2014 Feb 16. PubMed PMID: 24375454.

3: Williams TM, Nyati S, Ross BD, Rehemtulla A. Molecular imaging of the ATM kinase activity. Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):969-77. doi: 10.1016/j.ijrobp.2013.04.028. Epub 2013 May 29. PubMed PMID: 23726004; PubMed Central PMCID: PMC3710537.

4: Fallone F, Britton S, Nieto L, Salles B, Muller C. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression. Oncogene. 2013 Sep 12;32(37):4387-96. doi: 10.1038/onc.2012.462. Epub 2012 Oct 22. PubMed PMID: 23085754.

5: Wang H, Zuo B, Wang H, Ren L, Yang P, Zeng M, Duan D, Liu C, Li M. 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. doi: 10.1016/j.bbrc.2012.04.115. Epub 2012 Apr 30. PubMed PMID: 22564734.

6: Choi S, Toledo LI, Fernandez-Capetillo O, Bakkenist CJ. CGK733 does not inhibit ATM or ATR kinase activity in H460 human lung cancer cells. DNA Repair (Amst). 2011 Oct 10;10(10):1000-1; author reply 1002. doi: 10.1016/j.dnarep.2011.07.013. Epub 2011 Aug 23. PubMed PMID: 21865098; PubMed Central PMCID: PMC3189494.

7: Takahashi A, Mori E, Su X, Nakagawa Y, Okamoto N, Uemura H, Kondo N, Noda T, Toki A, Ejima Y, Chen DJ, Ohnishi K, Ohnishi T. ATM is the predominant kinase involved in the phosphorylation of histone H2AX after heating. J Radiat Res. 2010;51(4):417-22. Epub 2010 Apr 24. PubMed PMID: 20448412.

8: Alao JP, Sunnerhagen P. The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation. Radiat Oncol. 2009 Nov 10;4:51. doi: 10.1186/1748-717X-4-51. PubMed PMID: 19903334; PubMed Central PMCID: PMC2777912.

9: Normile D. Scientific misconduct. Science retracts discredited paper; bitter patent dispute continues. Science. 2009 Apr 24;324(5926):450-1. doi: 10.1126/science.324_450. PubMed PMID: 19390012.

10: Crescenzi E, Palumbo G, de Boer J, Brady HJ. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clin Cancer Res. 2008 Mar 15;14(6):1877-87. doi: 10.1158/1078-0432.CCR-07-4298. PubMed PMID: 18347191.

CGK733

100.0mg / USD 950.0


Additional Information

   CGK733 fraud
(copied from : http://en.wikipedia.org/wiki/CGK733_fraud)
    
CGK733 was a synthetic chemical substance which was reported in 2006 to have remarkable properties in reversing cell senescence (aging).  However, the entire work behind the discovery of this compound has since been found to be falsified and the authors of the original reports have retracted all their claims.
 
CGK733 was claimed to be an inhibitor of ATM/ATR kinases,  which are involved in DNA damage repair. CGK was claimed to extend the lifetime of cultured cells by approximately 20 divisions, or roughly 25%, specifically in mammalian cells.
 
The original report garnered scientific attention, but was retracted in 2008. The retraction states that the screen to identify CGK733 as an anti-senescence agent was not carried out; experiments exploring the cellular effects of CGK733 were misrepresented; the identification of ATM as the target of CGK733 was fabricated; a compound which was essential for ATM target validation had not been synthesized; and the chemical structure of CGK733 was misrepresented. The principal investigator, Tae Kook Kim, and several associates were consequently suspended from their positions at the Korea Advanced Institute of Science & Technology.