KU-55933
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MedKoo CAT#: 201681

CAS#: 587871-26-9

Description: KU-55933 is an ATM inhibitor, which blocks the phosphorylation of Akt induced by insulin and insulin-like growth factor I in cancer cells that exhibit abnormal Akt activity. Moreover, KU-55933 inhibits cancer cell proliferation by inducing G(1) cell cycle arrest. It does so through the downregulation of the synthesis of cyclin D1, a protein known to be elevated in a variety of tumors. In addition, KU-55933 treatment during serum starvation triggers apoptosis in these cancer cells. Research results suggest that KU-55933 may be a novel chemotherapeutic agent targeting cancer resistant to traditional chemotherapy or immunotherapy due to aberrant activation of Akt. Furthermore, KU-55933 completely abrogates rapamycin-induced feedback activation of Akt. Combination of KU-55933 and rapamycin not only induces apoptosis, which is not seen in cancer cells treated only with rapamycin, but also shows better efficacy in inhibiting cancer cell proliferation than each drug alone. For detail see: http://www.ncbi.nlm.nih.gov/pubmed/20053781.


Chemical Structure

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KU-55933
CAS# 587871-26-9

Theoretical Analysis

MedKoo Cat#: 201681
Name: KU-55933
CAS#: 587871-26-9
Chemical Formula: C21H17NO3S2
Exact Mass: 395.06498
Molecular Weight: 395.49
Elemental Analysis: C, 63.77; H, 4.33; N, 3.54; O, 12.14; S, 16.22

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 750.0 Same day
500.0mg USD 1250.0 Same day
1.0g USD 1950.0 Same day
2.0g USD 3250.0 2 Weeks
5.0g USD 5250.0 2 Weeks
10.0g USD 8950.0 2 Weeks
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Synonym: KU 55933; KU55933; KU-55933.

IUPAC/Chemical Name: 2-morpholino-6-(thianthren-1-yl)-4H-pyran-4-one

InChi Key: XRKYMMUGXMWDAO-UHFFFAOYSA-N

InChi Code: InChI=1S/C21H17NO3S2/c23-14-12-16(25-20(13-14)22-8-10-24-11-9-22)15-4-3-7-19-21(15)27-18-6-2-1-5-17(18)26-19/h1-7,12-13H,8-11H2

SMILES Code: O=C1C=C(N2CCOCC2)OC(C3=C4SC5=C(C=CC=C5)SC4=CC=C3)=C1

Appearance: White to off-white 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

Biological target: KU-55933 is a potent ATM inhibitor with an IC50 and Ki of 12.9 and 2.2 nM, respectively.
In vitro activity: These results indicate that KU-55933 has a detrimental effect on intracellular tachyzoite replication. However, the indirect effect of PI3K inhibitors on tachyzoite replication due to HFF alterations, specifically at high doses, cannot be ruled out. To investigate if KU-55933 can have an effect directly on Toxoplasma, extracellular tachyzoites were incubated 4 h in presence of different doses of KU-55933 at room temperature. After that HFF monolayers were infected and incubated in absence of the drug for 12 h. Figure 3E shows a significant reduction in tachyzoite replication from 2.5 μM, suggesting that KU-55933 has a direct impact on Toxoplasma. Reference: Front Cell Infect Microbiol. 2019; 9: 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381018/
In vivo activity: Treatment of DNA repair deficient Ercc1-/- MEFs with KU-55933 (10 μM) reduced the percent of SA-βgal positive cells to a level similar to WT MEFs (Figure 2A and 2B). Additional markers of senescence, including the cell-cycle regulators p21Cip1 and p16INK4A, also were decreased by KU-55933 treatment (Figure 2C). As expected, autophosphorylation of ATM at Ser1981 was downregulated by the ATM inhibitor, as were the levels of p-KAP1 and γH2AX (Figure 2D). Interestingly, ATM inhibition also decreased Poly [ADP-ribose] polymerase 1 (PARP1) abundance (Figure 2D), an enzyme that promotes DNA repair and chromatin remodeling, utilizing NAD+ as a cofactor. Interestingly, these results also suggest that inhibition of ATM activity may regulate ATM expression at protein level as indicated by reduced ATM level (Figure 2D). Furthermore, ATM inhibition reduced the abundance of nuclear-localized p65 and NEMO and the level of p-p65 (Figure 2E), as well as NF-κB transcriptional activity, measured using a NF-κB luciferase reporter assay (Figure 2F). Finally, treatment with the ATM inhibitor significantly reduced expression of multiple senescence and SASP markers as determined by qRT-PCR (Figure 2G). Taken together, these results suggest that ATM activation triggered by endogenous DNA damage plays a critical role in driving cellular senescence, SASP and NF-κB activation in a NEMO-dependent manner. Reference: Aging (Albany NY). 2020 Mar 31; 12(6): 4688–4710. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138542/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 42.14 106.55
DMF 30.0 75.86
DMF:PBS (pH 7.2) (1:1) 0.5 1.26
Ethanol 14.89 37.65

Preparing Stock Solutions

The following data is based on the product molecular weight 395.49 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
Formulation protocol: 1. Munera López J, Ganuza A, Bogado SS, Muñoz D, Ruiz DM, Sullivan WJ Jr, Vanagas L, Angel SO. Evaluation of ATM Kinase Inhibitor KU-55933 as Potential Anti-Toxoplasma gondii Agent. Front Cell Infect Microbiol. 2019 Feb 13;9:26. doi: 10.3389/fcimb.2019.00026. PMID: 30815397; PMCID: PMC6381018. 2. Li Y, Yang DQ. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010 Jan;9(1):113-25. doi: 10.1158/1535-7163.MCT-08-1189. Epub 2010 Jan 6. PMID: 20053781. 3. Zhao J, Zhang L, Lu A, Han Y, Colangelo D, Bukata C, Scibetta A, Yousefzadeh MJ, Li X, Gurkar AU, McGowan SJ, Angelini L, O'Kelly R, Li H, Corbo L, Sano T, Nick H, Pola E, Pilla SPS, Ladiges WC, Vo N, Huard J, Niedernhofer LJ, Robbins PD. ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging. Aging (Albany NY). 2020 Mar 22;12(6):4688-4710. doi: 10.18632/aging.102863. Epub 2020 Mar 22. PMID: 32201398; PMCID: PMC7138542. 4. Uehara M, Kusaba T, Ida T, Nakai K, Nakata T, Tomita A, Watanabe-Uehara N, Ikeda K, Kitani T, Yamashita N, Kirita Y, Matoba S, Humphreys BD, Tamagaki K. Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice. Sci Rep. 2020 Mar 10;10(1):4441. doi: 10.1038/s41598-020-61456-7. PMID: 32157166; PMCID: PMC7064514.
In vitro protocol: 1. Munera López J, Ganuza A, Bogado SS, Muñoz D, Ruiz DM, Sullivan WJ Jr, Vanagas L, Angel SO. Evaluation of ATM Kinase Inhibitor KU-55933 as Potential Anti-Toxoplasma gondii Agent. Front Cell Infect Microbiol. 2019 Feb 13;9:26. doi: 10.3389/fcimb.2019.00026. PMID: 30815397; PMCID: PMC6381018. 2. Li Y, Yang DQ. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010 Jan;9(1):113-25. doi: 10.1158/1535-7163.MCT-08-1189. Epub 2010 Jan 6. PMID: 20053781.
In vivo protocol: 1. Zhao J, Zhang L, Lu A, Han Y, Colangelo D, Bukata C, Scibetta A, Yousefzadeh MJ, Li X, Gurkar AU, McGowan SJ, Angelini L, O'Kelly R, Li H, Corbo L, Sano T, Nick H, Pola E, Pilla SPS, Ladiges WC, Vo N, Huard J, Niedernhofer LJ, Robbins PD. ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging. Aging (Albany NY). 2020 Mar 22;12(6):4688-4710. doi: 10.18632/aging.102863. Epub 2020 Mar 22. PMID: 32201398; PMCID: PMC7138542. 2. Uehara M, Kusaba T, Ida T, Nakai K, Nakata T, Tomita A, Watanabe-Uehara N, Ikeda K, Kitani T, Yamashita N, Kirita Y, Matoba S, Humphreys BD, Tamagaki K. Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice. Sci Rep. 2020 Mar 10;10(1):4441. doi: 10.1038/s41598-020-61456-7. PMID: 32157166; PMCID: PMC7064514.

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  1: Camins A, Pizarro JG, Alvira D, Gutierrez-Cuesta J, de la Torre AV, Folch J, Sureda FX, Verdaguer E, Junyent F, Jordán J, Ferrer I, Pallàs M. Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease. Cell Mol Life Sci. 2010 May 26. [Epub ahead of print] PubMed PMID: 20502937.

2: Pizarro JG, Folch J, de la Torre AV, Junyent F, Verdaguer E, Jordan J, Pallas

M, Camins A. ATM is involved in cell-cycle control through the regulation of retinoblastoma protein phosphorylation. J Cell Biochem. 2010 May;110(1):210-8. PubMed PMID: 20213763.

3: Rakkestad KE, Skaar I, Ansteinsson VE, Solhaug A, Holme JA, Pestka JJ, Samuelsen JT, Dahlman HJ, Hongslo JK, Becher R. DNA damage and DNA damage responses in THP-1 monocytes after exposure to spores of either Stachybotrys chartarum or Aspergillus versicolor or to T-2 toxin. Toxicol Sci. 2010 May;115(1):140-55. Epub 2010 Feb 11. PubMed PMID: 20150440.

4: Li Y, Yang DQ. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010 Jan;9(1):113-25. Epub 2010 Jan 6. PubMed PMID: 20053781.

5: Chalmers AJ, Ruff EM, Martindale C, Lovegrove N, Short SC. Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent. Int J Radiat

Oncol Biol Phys. 2009 Dec 1;75(5):1511-9. PubMed PMID: 19931733.

6: Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O'Connor MJ, Povirk LF, van Meter

T, Valerie K. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009 Oct;8(10):2894-902. Epub 2009 Oct 6. PubMed PMID: 19808981; PubMed Central PMCID: PMC2761990.

7: Xue L, Yu D, Furusawa Y, Cao J, Okayasu R, Fan S. ATM-dependent hyper-radiosensitivity in mammalian cells irradiated by heavy ions. Int J Radiat

Oncol Biol Phys. 2009 Sep 1;75(1):235-43. PubMed PMID: 19695441.

8: Collaco RF, Bevington JM, Bhrigu V, Kalman-Maltese V, Trempe JP. Adeno-associated virus and adenovirus coinfection induces a cellular DNA damage and repair response via redundant phosphatidylinositol 3-like kinase pathways. Virology. 2009 Sep 15;392(1):24-33. Epub 2009 Jul 23. PubMed PMID: 19628243; PubMed Central PMCID: PMC2742906.

9: Wang Z, Wang M, Kar S, Carr BI. Involvement of ATM-mediated Chk1/2 and JNK kinase signaling activation in HKH40A-induced cell growth inhibition. J Cell Physiol. 2009 Oct;221(1):213-20. PubMed PMID: 19530246.

10: Kumari D, Somma V, Nakamura AJ, Bonner WM, D'Ambrosio E, Usdin K. The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome. Nucleic Acids Res. 2009 Jul;37(13):4385-92. Epub 2009 May 21. PubMed PMID: 19465392; PubMed Central PMCID: PMC2715245.

11: Zhang YW, Jones TL, Martin SE, Caplen NJ, Pommier Y. Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response. J Biol Chem. 2009 Jul 3;284(27):18085-95. Epub 2009 May 5. PubMed PMID: 19416980; PubMed Central PMCID: PMC2709352.

KU-55933

25.0mg / USD 150.0


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