Synonym
KU-0060648; KU 0060648; KU0060648.
IUPAC/Chemical Name
4-Ethyl-N-[4-[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]-1-dibenzothienyl]-1-piperazineacetamide
InChi Key
AATCBLYHOUOCTO-UHFFFAOYSA-N
InChi Code
InChI=1S/C33H34N4O4S/c1-2-35-12-14-36(15-13-35)21-29(39)34-26-11-10-23(33-31(26)25-6-3-4-9-28(25)42-33)22-7-5-8-24-27(38)20-30(41-32(22)24)37-16-18-40-19-17-37/h3-11,20H,2,12-19,21H2,1H3,(H,34,39)
SMILES Code
O=C1C=C(N2CCOCC2)OC3=C(C4=C5C(C6=CC=CC=C6S5)=C(NC(CN7CCN(CC7)CC)=O)C=C4)C=CC=C13
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:
ATP-competitive inhibitor of DNA-dependent protein kinase (DNA-PK) and an inhibitor of PI3K.
In vitro activity:
KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon
cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and
0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells) and more
than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 95% in MCF7
cells but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and
doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced
cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were
sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor for at least 4 hours at nontoxic
doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in
SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof-of-principle
in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.
Reference: Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin
RJ, Menear K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by KU0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012 Aug;11(8):1789-98. doi: 10.1158/1535-7163.MCT-11-
0535. Epub 2012 May 10. PMID: 22576130; PMCID: PMC3428850.
In vivo activity:
In vivo, intraperitoneal (i.p.) injection of KU-0060648 significantly inhibited HepG2 xenograft growth in nude mice. AKT-mTOR
activation was also inhibited in xenografted tumors. Finally, it was shown that DNA-PKcs expression was significantly upregulated in
human HCC tissues. Yet miRNA-101, an anti-DNA-PKcs miRNA, was downregulated. Over-expression of miR-101 in HepG2 cells
inhibited DNA-PKcs expression and cell proliferation. Together, these results indicate that KU-0060648 inhibits HCC cells through
DNA-PKcs-dependent and -independent mechanisms.
Reference: Chen MB, Zhou ZT, Yang L, Wei MX, Tang M, Ruan TY, Xu JY, Zhou XZ, Chen G, Lu PH. KU-0060648 inhibits
hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms. Oncotarget. 2016 Mar
29;7(13):17047-59. doi: 10.18632/oncotarget.7742. PMID: 26933997; PMCID: PMC4941370.
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
1.0 |
1.72 |
| DMF |
1.0 |
1.72 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
582.72
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.
| 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:
Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear
K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by KU-0060648, a dual
inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012 Aug;11(8):1789-98. doi: 10.1158/1535-7163.MCT-11-0535. Epub 2012
May 10. PMID: 22576130; PMCID: PMC3428850.
In vitro protocol:
Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear
K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by KU-0060648, a dual
inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012 Aug;11(8):1789-98. doi: 10.1158/1535-7163.MCT-11-0535. Epub 2012
May 10. PMID: 22576130; PMCID: PMC3428850.
In vivo protocol:
Chen MB, Zhou ZT, Yang L, Wei MX, Tang M, Ruan TY, Xu JY, Zhou XZ, Chen G, Lu PH. KU-0060648 inhibits hepatocellular
carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms. Oncotarget. 2016 Mar 29;7(13):17047-59.
doi: 10.18632/oncotarget.7742. PMID: 26933997; PMCID: PMC4941370.
1: Chen MB, Zhou ZT, Yang L, Wei MX, Tang M, Ruan TY, Xu JY, Zhou XZ, Chen G, Lu
PH. KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent
and DNA-PKcs-independent mechanisms. Oncotarget. 2016 Feb 26. doi:
10.18632/oncotarget.7742. [Epub ahead of print] PubMed PMID: 26933997.
2: Robert F, Barbeau M, Éthier S, Dostie J, Pelletier J. Pharmacological
inhibition of DNA-PK stimulates Cas9-mediated genome editing. Genome Med. 2015
Aug 27;7:93. doi: 10.1186/s13073-015-0215-6. PubMed PMID: 26307031; PubMed
Central PMCID: PMC4550049.
3: Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M,
Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin
NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by
KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012
Aug;11(8):1789-98. doi: 10.1158/1535-7163.MCT-11-0535. Epub 2012 May 10. PubMed
PMID: 22576130; PubMed Central PMCID: PMC3428850.
