A8336-10mg | KU-60019 [925701-49-1] Clinisciences

KU-60019 is a selective inhibitor of the Ataxia telangiectasia (A-T) mutated (ATM) protein with an IC50 value of 6.3 nM. In literature report, KU-60019 radiosensitizes h-TERT-immortalized normal fibroblasts but not A-T fibroblasts, suggesting it is a specific ATM kinase radiosensitizer [1].

KU-60019 can reduce radiation-induced S473 AKT phosphorylation in human glioma cell lines that are p53 wild type (U87) and p53 mutant (U1242). However, the suppression of AKT does not enhance radiosensitization of KU-60019 [1].

KU-60019 has been reported to inhibit cell migration and invasion in human glioma cells U87 and U1242 in a dose-dependent manner. Besides, KU-60019, to some extent, has also been shown to suppress the growth of U1242 cells [1].

References:
[1] Golding SE1, 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.

1. Yaru Zhang, Marco Jost, et al. "Adaptive exchange sustains cullin–RING ubiquitin ligase networks and proper licensing of DNA replication." Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2205608119. PMID: 36037385
2. Mathew J.K. Jones, Camille Gelot, et al. "Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication." Mol Cell. 2021 Feb 4;81(3):426-441.e8. PMID:33545059
3. Zheng K, Ma J, et al. "Sulforaphane Inhibits Autophagy and Induces Exosome-Mediated Paracrine Senescence via Regulating mTOR/TFE3." Mol Nutr Food Res. 2020;e1901231. PMID:32476238
4. Zhao K, Wang X, et al. "A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers." PLoS Biol. 2020;18(3):e3000666. PMID:32203529
5. Christine Wenz. "Cell confluence as crucial regulator of ROS-induced toxicity: Analysis of t-BuOOH-induced cell death in vitro." Gutenberg-Universität in Mainz. 2019.
6. Caster JM, Yu SK, et al. "Effect of particle size on the biodistribution, toxicity, and efficacy of drug-loaded polymeric nanoparticles in chemoradiotherapy." Nanomedicine. 2017 Mar 11. pii: S1549-9634(17)30044-8. PMID:28300658
7. Mignon Albertha van Vuuren. "The role of Atm in the regulation of cardiomyocyte glucose utilization under normal and insulin resistant conditions." Stellenbosch University. March 2016.

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Storage	Store at -20°C
M.Wt	547.68
Cas No.	925701-49-1
Formula	C₃₀H₃₃N₃O₅S
Synonyms	KU60019;KU 60019
Solubility	≥27.4 mg/mL in DMSO; insoluble in H2O; ≥51.2 mg/mL in EtOH
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
SDF	Download SDF
Canonical SMILES	CC1CN(CC(O1)C)CC(=O)NC2=CC3=C(C=C2)SC4=C(C=CC=C4C3)C5=CC(=O)C=C(O5)N6CCOCC6
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Cell experiment [1]:
Cell lines	U87 and U1242 cells
Preparation method	The solubility of this compound in DMSO is > 27.4 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
Reacting condition	3 μM; 1, 3 and 5 days
Applications	In U87 cells, KU-60019 at 3 μM significantly inhibited cell migration and invasion by > 70% and ~ 60%, respectively. Similarly, KU-60019 also substantially inhibited migration and invasion of human glioma U1242 cells by > 50% and ~ 60%, respectively.
Animal experiment [2]:
Animal models	Athymic female mice implanted with U1242/luc-GFP cells
Dosage form	KU-60019 (10 μM) delivered intratumorally at a rate of 0.5 μL/h by osmotic pump, for 14 days
Applications	In athymic female mice implanted with U1242/luc-GFP cells, the combination of KU-60019 and radiation significantly inhibited tumor growth than radiation alone, which suggested that KU-60019 might radiosensitize U1242 gliomas.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Golding SE1, 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. [2]. Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NC, Tokarz M, Adams BR, Wagner AF, Khalil A, Gilfor D, Golding SE, Deb S, Temesi DG, Lau A, O'Connor MJ, Choe KS, Parada LF, Lim SK, Mukhopadhyay ND, Valerie K. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin Cancer Res. 2013 Jun 15;19(12):3189-200.

Description	KU-60019 is an improved analogue of KU-55933 with IC50 of 6.3 nM for ATM, 270- and 1600-fold more selective for ATM than DNA-PK and ATR.
Targets	ATM
IC50	6.3 nM