KU-60019

Alias: KU60019; KU 60019; KU-60019

Cat No.:V2526 Purity: ≥98%

COA Product Data Instructions for use SDS

KU-60019 is an improved analogue of KU-55933 with 10-fold higher activity than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells.

KU-60019 Chemical Structure CAS No.: 925701-49-1
Product category: ATM(ATR)

This product is for research use only, not for human use. We do not sell to patients.

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Citations by Top Journals: Nature, Cell, Science, etc.

Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

NMR

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

KU-60019 is an improved analogue of KU-55933 with 10-fold higher activity than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. It is a very potent radiosensitizer with an IC50 of 6.3 nM for ATM in cell-free assays, and it is 270 and 1600 times more selective for ATM than DNA-PK and ATR. In human glioma cell lines that are p53 wild type (U87) and p53 mutant (U1242), KU-60019 can decrease radiation-induced S473 AKT phosphorylation. But AKT suppression does not improve KU-60019's radiosensitization. In human glioma cells U87 and U1242, KU-60019 has been shown to inhibit cell migration and invasion in a dose-dependent manner. Furthermore, it has been demonstrated that KU-60019 can inhibit the growth of U1242 cells to a certain degree.

Biological Activity I Assay Protocols (From Reference)

Targets

ATM ( IC50 = 6.3 nM ); DNA-PKcs ( IC50 = 1.7 μM )

ln Vitro

In vitro activity: In contrast to KU-55933, KU-60019 exhibits similar target selectivity but is a better ATM kinase inhibitor. KU-60019 exhibits negligible efficacy against 229 protein kinases, including PI3K, mTOR, and mTOR/FKBP12, and DNA-PKcs and ATR, with IC50 values of 1.7 μM and >10 μM, respectively. In human glioma U87 and U1242 cells, KU-60019 exhibits 3- to 10-fold greater potency than KU-55933 at inhibiting radiation-induced phosphorylation of important ATM protein targets, including p53, γ-H2AX, and CHK2. This is because 1 μM of KU-60019 significantly reduces p53 (S15) phosphorylation by >70%, a reduction that requires ~10 μM of KU-55933 to attain. In addition to radiosensitizing human glioma cells, KU-60019 also radiosensitizes normal fibroblasts but not A-T fibroblasts, with dose-enhancement ratios of 1.7 and 4.4 at 1 μM and 10 μM, respectively. Treatment with KU-60019 (3 μM) completely reduces radiation-induced AKT phosphorylation below the control level and blocks 70% of basal and ~50% of insulin-induced AKT S473 phosphorylation, respectively. The phosphorylase inhibitor okadaic acid significantly blocks the effect of KU-60019 on AKT S473 phosphorylation in glioma cell lines and normal fibroblasts, but not in A-T (h-TERT) cells. This suggests a critical role for ATM kinase in regulating AKT phosphorylation via unknown phosphatase. KU-60019 at 3 μM significantly inhibits the migration and invasion of human glioma U87 cells by >70% and ~60%, respectively, and U1242 cells by >50% and ~60%, respectively, which is consistent with the inhibition of prosurvival AKT signaling. [1]

ln Vivo

Radiation plus KU-60019 greatly increases mouse survival in orthotopic glioma U1242/luc-GFP xenograft models compared to radiation alone, KU-60019 alone, or no treatment at all. Furthermore, p53-mutant gliomas respond far more strongly to KU-60019 radiosensitization than do gliomas of the wild type.[2]

Cell Assay

KU-60019 is exposed to cells for 1, 3, and 5 days. AlamarBlue is the measure of cell growth. The medium is supplemented with AlamarBlue up to the suggested final concentration. The Fluoro-Count plate reader (excitation 530 nm, emission 590 nm) is used to measure fluorescence on the plates after an hour of incubation at 37 °C. The values obtained represent the growth of the cells. The trypan blue/fluorescence activated cell sorting (FACS) assay is used to assess cell survival.

Animal Protocol

Mice: Male Fox Chase Severe Combined Immunodeficiency (SCID) mice are implanted with cells (3×10⁷). Doxycycline is given every 48 hours until the animal is removed from the experiment, beginning when the tumor reaches a volume of 100 mm³. Animals are given 100 mg/kg of KU-60019 for five days in a row following PTEN induction, and their volume is measured every day until the animals reach the 400 mm³ target. Every three days, the tumor volume and body weight were measured with calipers.

References

[1]. 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.

[2]. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM. Cancer Res. 2015 Jun 1;75(11):2159-65.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula

C30H33N3O5S

Molecular Weight

547.67

Exact Mass

547.21

CAS #

925701-49-1

Related CAS #

925701-49-1

Appearance

Powder

SMILES

C[C@@H]1CN(C[C@@H](O1)C)CC(=O)NC2=CC3=C(C=C2)SC4=C(C3)C=CC=C4C5=CC(=O)C=C(O5)N6CCOCC6

InChi Key

SCELLOWTHJGVIC-BGYRXZFFSA-N

InChi Code

InChI=1S/C30H33N3O5S/c1-19-16-32(17-20(2)37-19)18-28(35)31-23-6-7-27-22(13-23)12-21-4-3-5-25(30(21)39-27)26-14-24(34)15-29(38-26)33-8-10-36-11-9-33/h3-7,13-15,19-20H,8-12,16-18H2,1-2H3,(H,31,35)/t19-,20+

Chemical Name

2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-N-[5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen-2-yl]acetamide

Synonyms

KU60019; KU 60019; KU-60019

Storage

Powder -20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)

DMSO: 18~100 mg/mL (32.9~182.6 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In Vivo)

5%DMSO+ 40%PEG300+5%Tween 80+50%ddH2O: 5.0mg/ml (9.13mM) (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8259 mL	9.1296 mL	18.2592 mL
	5 mM	0.3652 mL	1.8259 mL	3.6518 mL
	10 mM	0.1826 mL	0.9130 mL	1.8259 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Biological Data

KU-60019 is a more effective inhibitor of the ATM kinase than KU-55933.Mol Cancer Ther.2009 Oct;8(10):2894-902.
KU-60019 radiosensitizes U87 and U1242 human glioma cells and normal but not A-T fibroblasts.Mol Cancer Ther.2009 Oct;8(10):2894-902.
KU-60019 inhibits migration and invasion of human glioma U87 and U1242 cells in vitro.Mol Cancer Ther.2009 Oct;8(10):2894-902.