| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
KU59403 targets the ATM kinase, a serine/threonine protein kinase that plays a central role in the cellular response to DNA double-strand breaks (DSBs). It inhibits ATM with an IC50 of 3 nM. The compound shows high selectivity for ATM over related kinases, with IC50 values of 9.1 µM for DNA-PK and 10 µM for PI3K. By inhibiting ATM, KU59403 blocks the activation of downstream cell-cycle checkpoints and DNA repair pathways, leading to the accumulation of unrepaired DNA damage in cancer cells.
|
|---|---|
| ln Vitro |
KU 59403 (1 μM) exhibits a sensitization of 11.9 in p53 mutant SW620 cells and the human breast cancer cell line MDAMB-231, while also potentiating VP-16 (1 μM) cytotoxicity in HCT116 and HCT116-N7 cells to a comparable degree. ±4.7 and 3.8±1.8 times, in that order. In MDA-MB231 cells, which have lower ATM expression and activity, KU 59403 (1 μM) inhibited IR-induced ATM activity by roughly 50%, whereas in HCT116 cells, it was more than 50% [1].
In vitro, KU59403 is not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116, and MDA-MB-231) when used alone. However, it significantly increases the cytotoxicity of topoisomerase I and II poisons, including camptothecin, etoposide, and doxorubicin. The compound enhances the sensitivity of cancer cells to these DNA-damaging agents in a concentration-dependent manner, with the potentiation effect being more pronounced in cells with functional p53. KU59403 also abrogates the G2/M checkpoint and reduces the phosphorylation of ATM substrates such as CHK2 and p53 following DNA damage. |
| ln Vivo |
At a single daily dosage of 12.5 mg/kg, KU59403 significantly sensitizes the body [1]. The KU59403 dose was increased to 25 mg/kg twice day, which produced maximal chemosensitivity and a three-fold increase in the tumor growth delay induced by BMY-40481 in SW620 and HCT116-N7 xenografts without causing considerable chemosensitivity. elevated toxicity [1].
In vivo, KU59403 significantly enhances the antitumor activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116). The compound is administered orally and is well-tolerated in combination with chemotherapeutic agents at doses that are non-toxic when used alone. KU59403 potentiates the efficacy of irinotecan and doxorubicin, leading to increased tumor growth inhibition and, in some cases, tumor regression. The combination treatment does not result in enhanced host toxicity, indicating a favorable therapeutic index for this ATM inhibitor in preclinical models. |
| Enzyme Assay |
The non-cellular assay for KU59403 involves measuring its inhibitory activity against ATM kinase using in vitro kinase assays. Recombinant ATM protein is incubated with a substrate peptide and ATP in the presence of varying concentrations of the compound. The phosphorylation of the substrate is quantified using radioactive or luminescent detection methods. The IC50 is determined from concentration-response curves. Selectivity is assessed by profiling KU59403 against a panel of related kinases, including DNA-PK and PI3K, using similar biochemical assays.
|
| Cell Assay |
Cell viability assay[1]
Cell Types: LoVo, HCT116 and SW620 (human colon cancer), U2OS (human osteosarcoma) and MDA-MB-231 (human breast cancer) cells. Tested Concentrations: 1μM. Incubation Duration: 16 hrs (hours). Experimental Results: ATM was at least 1000-fold more specific than other members of the PI3K family tested. Camptothecin cytotoxicity was enhanced in both cell lines, with a greater enhancement observed in LoVo cells compared with SW620 cells. Dramatically enhances the cytotoxicity of fixed concentrations of VP-16 (0.1 and 1 μM) or NSC 123127 (10 or 100 nM) in these cell lines, with VP-16 in SW620 cells and NSC 123127 in LoVo cells. The effect is greater. The cellular assay for KU59403 evaluates its ability to sensitize cancer cells to DNA-damaging agents. Human cancer cell lines (e.g., SW620, HCT116) are treated with KU59403 alone or in combination with topoisomerase poisons. Cell viability is assessed using standard assays such as MTT or colony formation assays. The phosphorylation of ATM substrates (e.g., CHK2, p53) is measured by Western blotting to confirm target inhibition. Cell cycle analysis by flow cytometry is used to assess checkpoint abrogation. |
| Animal Protocol |
Animal/Disease Models: CD-1 nude mice were subcutaneously (sc) (sc) implanted with SW620 or HCT116-N7 human cancer cell lines, with 1×107 cells per animal (n=5 per group) [1].
Doses: 6, 12.5 and 25 mg/kg. Dosing: 12.5 mg/kg IP twice (two times) daily (0 hrs (hrs (hours)) and 4 hrs (hrs (hours))), one time/day. Experimental Results: Treatment with BMY-40481 alone resulted in a modest delay in tumor growth of 4 days (time to RTV4 = 10.5 days). This delay extended to 8.5 days when KU 59403 was administered intraperitoneally (ip) (ip) at 12.5 mg/kg twice (two times) daily for 5 days and to 11.5 when KU 59403 was administered intraperitoneally (ip) (ip) at 25 mg/kg twice (two times) daily for 5 days. days (time to reach RTV4 = 18 days). In the in vivo efficacy study, female BALB/c nude mice bearing subcutaneous human colon cancer xenografts (SW620 or HCT116) are treated with KU59403 orally at various doses, alone or in combination with topoisomerase poisons (e.g., irinotecan or doxorubicin). Tumor volumes are measured twice weekly, and body weight is monitored as a toxicity indicator. At the end of the study, tumors are harvested for pharmacokinetic and pharmacodynamic analysis, including assessment of ATM phosphorylation and DNA damage markers. |
| ADME/Pharmacokinetics |
KU59403 is soluble in DMSO but not in water. It has a molecular weight of 564.72 and a molecular formula of C₂₉H₃₂N₄O₄S₂. The compound should be stored at 0-4°C for short-term use or at -20°C for long-term storage. In vivo pharmacokinetic studies indicate that KU59403 has favorable oral bioavailability, with systemic exposure sufficient to achieve target inhibition in tumor tissues. The compound's half-life supports once- or twice-daily dosing in preclinical models.
|
| Toxicity/Toxicokinetics |
KU59403 is well-tolerated in mice at doses that produce significant tumor sensitization, with no overt toxicity observed when used alone. In combination with topoisomerase poisons, the compound does not exacerbate host toxicity, as indicated by stable body weights and absence of clinical signs of distress. Comprehensive toxicology studies beyond these preclinical findings are limited, as KU59403 is a research compound and not approved for clinical use.
|
| References | |
| Additional Infomation |
KU59403 was identified as an ATM inhibitor with the potency, selectivity, and solubility for advanced preclinical evaluation. It was developed by researchers and published in Molecular Cancer Therapeutics in 2013. By inhibiting ATM, KU59403 sensitizes cancer cells to DNA-damaging agents, making it a valuable tool for studying the role of ATM in the DNA damage response and for validating ATM as a therapeutic target for combination cancer therapy. The compound is not approved for clinical use and is strictly a research tool.
|
| Molecular Formula |
C29H32N4O4S2
|
|---|---|
| Molecular Weight |
564.72
|
| Exact Mass |
564.186
|
| CAS # |
845932-30-1
|
| PubChem CID |
11433009
|
| Appearance |
White to yellow solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Boiling Point |
814.3±65.0 °C at 760 mmHg
|
| Flash Point |
446.3±34.3 °C
|
| Vapour Pressure |
0.0±2.9 mmHg at 25°C
|
| Index of Refraction |
1.683
|
| LogP |
4.48
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
39
|
| Complexity |
963
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CN1CCN(CC1)CCC(=O)NC2=CC3=C(C=C2)SC4=C(C=CC=C4S3)C5=CC(=O)C=C(O5)N6CCOCC6
|
| InChi Key |
IIBZKDYAYJSSGB-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C29H32N4O4S2/c1-31-9-11-32(12-10-31)8-7-27(35)30-20-5-6-24-26(17-20)38-25-4-2-3-22(29(25)39-24)23-18-21(34)19-28(37-23)33-13-15-36-16-14-33/h2-6,17-19H,7-16H2,1H3,(H,30,35)
|
| Chemical Name |
3-(4-methylpiperazin-1-yl)-N-[6-(6-morpholin-4-yl-4-oxopyran-2-yl)thianthren-2-yl]propanamide
|
| Synonyms |
KU 59403; KU-59403; KU59403
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~10 mg/mL (~17.71 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7708 mL | 8.8539 mL | 17.7079 mL | |
| 5 mM | 0.3542 mL | 1.7708 mL | 3.5416 mL | |
| 10 mM | 0.1771 mL | 0.8854 mL | 1.7708 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.
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.
(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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
