KU-0060648

Dual DNA-PK/PI3-K inhibitor, ATP-competitive CAS# 881375-00-4

KU-0060648

Catalog No. BCC1110----Order now to get a substantial discount!

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Chemical structure

KU-0060648

3D structure

Chemical Properties of KU-0060648

Cas No. 881375-00-4 SDF Download SDF
PubChem ID 11964036 Appearance Powder
Formula C33H34N4O4S M.Wt 582.71
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in 2eq.HCl
Chemical Name 2-(4-ethylpiperazin-1-yl)-N-[4-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-1-yl]acetamide
SMILES CCN1CCN(CC1)CC(=O)NC2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7
Standard InChIKey AATCBLYHOUOCTO-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of KU-0060648

DescriptionDual PI 3-K and DNA-PK inhibitor (IC50 values are <0.1, 0.5, 4 and 19 nM for PI 3-Kδ, PI 3-Kβ, PI 3-Kα and DNA-PK respectively). Inhibits proliferation of MCF7 cells in vitro and delays growth of MCF7 xenografts in mice. Also enhances CRISPR-Cas9-mediated homology-directed repair (HDR) efficiency ~2 to 4-fold, and decreases nonhomologous end-joining (NHEJ) frequency ~40%; maximum effect seen at 250 nM.

KU-0060648 Dilution Calculator

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KU-0060648 Molarity Calculator

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Preparing Stock Solutions of KU-0060648

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7161 mL 8.5806 mL 17.1612 mL 34.3224 mL 42.903 mL
5 mM 0.3432 mL 1.7161 mL 3.4322 mL 6.8645 mL 8.5806 mL
10 mM 0.1716 mL 0.8581 mL 1.7161 mL 3.4322 mL 4.2903 mL
50 mM 0.0343 mL 0.1716 mL 0.3432 mL 0.6864 mL 0.8581 mL
100 mM 0.0172 mL 0.0858 mL 0.1716 mL 0.3432 mL 0.429 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on KU-0060648

IC50: KU-0060648 inhibited cellular DNA-PK autophosphorylation with IC50 values of 0.17 μmol/L (SW620 cells) and 0.019 μmol/L (MCF7 cells), and PI-3K–mediated AKT phosphorylation with IC50 values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells).
DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs), which promotes cell survival and proliferation and is upregulated in many cancers, is structurally similar to PI-3K,. KU-0060648 is a dual inhibitor of DNA-PKand PI-3K in vitro.
In vitro: KU-0060648 was investigated in a panel ofhumanbreast and colon cancer cells. Five-day exposure to 1 μM KU-0060648 was found to inhibite cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. KU-0060648 increased the etoposide and doxorubicin cytotoxicity across the DNA-PKcs–proficient cell panel rather than in DNA-PKcs–deficient cells, therefore confirming the enhanced cytotoxicity was due to the inhibition of DNA-PK [1].
In vivo: In mice bearing SW620 and MCF7 xenografts, KU-0060648 concentrations that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor at nontoxic doses for at least 4 hours. KU-0060648 alone delayed the MCF7 xenografts growth and increased etoposide-induced tumor growth delay in both in MCF7 and SW620 xenografts by up to 4.5 folds, without causing etoposide toxicity to unacceptable levels [1].
Clinical trial: KU-0060648 is still in pre-clinical development stage and no clinicl trial is ongoing currently.
Reference:
[1] 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;11(8):1789-98.

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References on KU-0060648

Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K.[Pubmed:22576130]

Mol Cancer Ther. 2012 Aug;11(8):1789-98.

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. 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 mumol/L (MCF7 cells) and 0.17 mumol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 mumol/L (MCF7 cells) and more than 10 mumol/L (SW620 cells). Five-day exposure to 1 mumol/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.

KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms.[Pubmed:26933997]

Oncotarget. 2016 Mar 29;7(13):17047-59.

Here we tested anti-tumor activity of KU-0060648 in preclinical hepatocellular carcinoma (HCC) models. Our results demonstrated that KU-0060648 was anti-proliferative and pro-apoptotic in established (HepG2, Huh-7 and KYN-2 lines) and primary human HCC cells, but was non-cytotoxic to non-cancerous HL-7702 hepatocytes. DNA-PKcs (DNA-activated protein kinase catalytic subunit) is an important but not exclusive target of KU-0060648. DNA-PKcs knockdown or dominant negative mutation inhibited HCC cell proliferation. On the other hand, overexpression of wild-type DNA-PKcs enhanced HepG2 cell proliferation. Importantly, KU-0060648 was still cytotoxic to DNA-PKcs-silenced or -mutated HepG2 cells, although its activity in these cells was relatively weak. Further studies showed that KU-0060648 inhibited PI3K-AKT-mTOR activation, independent of DNA-PKcs. Introduction of constitutively-active AKT1 (CA-AKT1) restored AKT-mTOR activation after KU-0060648 treatment in HepG2 cells, and alleviated subsequent cytotoxicity. 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, we showed 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.

Pharmacological inhibition of DNA-PK stimulates Cas9-mediated genome editing.[Pubmed:26307031]

Genome Med. 2015 Aug 27;7:93.

BACKGROUND: The ability to modify the genome of any cell at a precise location has drastically improved with the recent discovery and implementation of CRISPR/Cas9 editing technology. However, the capacity to introduce specific directed changes at given loci is hampered by the fact that the major cellular repair pathway that occurs following Cas9-mediated DNA cleavage is the erroneous non-homologous end joining (NHEJ) pathway. Homology-directed recombination (HDR) is far less efficient than NHEJ and makes screening of clones containing directed changes time-consuming and labor-intensive. METHODS: We investigated the possibility of pharmacologically inhibiting DNA-PKcs, a key player in NHEJ, using small molecule inhibitors (NU7441 and KU-0060648), to ameliorate the rates of HDR repair events. These compounds were tested in a sensitive reporter assay capable of simultaneously informing on NHEJ and HDR, as well as on an endogenous gene targeted by Cas9. RESULTS: We find that NU7441 and KU-0060648 reduce the frequency of NHEJ while increasing the rate of HDR following Cas9-mediated DNA cleavage. CONCLUSIONS: Our results identify two small molecules compatible for use with Cas9-editing technology to improve the frequency of HDR.

Radiosensitising agents for the radiotherapy of cancer: novel molecularly targeted approaches.[Pubmed:19456277]

Expert Opin Ther Pat. 2009 Jun;19(6):775-99.

BACKGROUND: The efficacy of radiotherapy (RT) for cancer treatment is limited by normal tissue toxicity and by the intrinsic or acquired radioresistance of many tumours. Therefore, continuing efforts are conducted to identify radiosensitising agents that preferentially sensitise tumour cells to the cytotoxic action of RT. Recent progresses in molecular oncology have uncovered an array of novel targets, which may be exploited for RT enhancement. OBJECTIVE: To survey the patent literature of the past 4 years pertaining to the development of molecularly targeted agents as potential tumour radiosensitisers. METHODS: Patents were searched with a set of relevant keywords using several search engines. A Medline search on the same topics was performed in parallel. RESULTS/CONCLUSION: A total of 48 patents/applications were selected. These concerned agents target molecular components of pathways involved in DNA damage repair, cell growth and survival signalling, apoptosis modulation and tumour angiogenesis. Current trials of some of these agents may reveal their value as clinical radiosensitisers.

Description

KU-0060648 is a dual inhibitor of PI3K and DNA-PK with IC50s of 4 nM, 0.5 nM, 0.1 nM, 0.594 nM and 8.6 nM for PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and DNA-PK, respectively.

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