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

• ChemBase ID: 72749
• Molecular Formular: C30H33N3O5S
• Molecular Mass: 547.66512
• Monoisotopic Mass: 547.21409217
• SMILES: c1c(ccc2c1Cc1c(S2)c(ccc1)c1cc(=O)cc(o1)N1CCOCC1)NC(=O)CN1C[C@@H](O[C@@H](C1)C)C
• Canonical SMILES: O=C(Nc1ccc2c(c1)Cc1c(S2)c(ccc1)c1cc(=O)cc(o1)N1CCOCC1)CN1C[C@H](C)O[C@@H](C1)C
• InChI: 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+
• InChIKey: SCELLOWTHJGVIC-BGYRXZFFSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-{5-[6-(morpholin-4-yl)-4-oxo-4H-pyran-2-yl]-9H-thioxanthen-2-yl}acetamide
• IUPAC Traditional name: 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-{5-[6-(morpholin-4-yl)-4-oxopyran-2-yl]-9H-thioxanthen-2-yl}acetamide
• Synonyms: KU-60019

Database IDs

• CAS Number: 925701-49-1
• PubChem SID: 162037670
• PubChem CID: 15953870

CALCULATED PROPERTIES

• Acid pKa: 13.389913
• H Acceptors: 7
• H Donor: 1
• LogD (pH = 5.5): 3.6218374
• LogD (pH = 7.4): 4.0275607
• Log P: 4.0361686
• Molar Refractivity: 166.2658 cm^3
• Polarizability: 58.70665 Å^3
• Polar Surface Area: 80.34 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: ATM

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1570

Research Area

• Description: Cancer

Biological Activity

• Description: KU-60019 is a potent and specific ATM inhibitor with IC50 of 6.3 nM.
• Targets: ATM
• IC50: 6.3 nM ^[1]
• In Vitro: Compared to KU-55933, KU-60019 is an improved more water-soluble inhibitor of the ATM kinase, while displaying similar target selectivity. KU-60019 has little activity against DNA-PKcs and ATR with IC50 values of 1.7 μM and >10 μM, respectively, as well as 229 other protein kinases such as PI3K, mTOR and mTOR/FKBP12. KU-60019 displays 3- to 10-fold more potency than KU-55933 at blocking radiation-induced phosphorylation of key ATM protein targets such as p53, γ-H2AX, and CHK2, in human glioma U87 and U1242 cells, as 1 μM of KU-60019 significantly induces >70% decrease of p53 (S15) phosphorylation to which extent ~10 μM of KU-55933 is required to achieve. KU-60019 effectively radiosensitizes human glioma cells with dose-enhancement ratio of 1.7 and 4.4 at 1 μM and 10 μM, respectively, and also radiosensitizes the normal fibroblasts but not the A-T fibroblasts. KU-60019 treatment (3 μM) blocks basal and insulin-induced AKT S473 phosphorylation by 70% and ~50%, respectively, and completely reduces radiation-induced AKT phosphorylation below the level of control. The effect of KU-60019 on AKT S473 phosphorylation can be seen in glioma cell lines and normal fibroblasts but not in A-T (h-TERT) cells, and can be significantly blocked by phosphatase inhibitor okadaic acid, suggesting a critical role of ATM kinase in regulating AKT phosphorylation via unknown phosphatase. Consistent with the inhibition of prosurvival AKT signaling, KU-60019 at 3 μM significantly inhibits migration and invasion of human glioma U87 cells by >70% and ~60%, respectively, as well as U1242 cells by >50% and ~60% respectively. ^[1]
• Features: An improved analog of KU-55933, more effective at blocking ATM-mediated DDR events.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: U87 and U1242
• Concentrations: Dissolved in water, final concentrations ~3 μM
• Incubation Time: 1, 3, and 5 days
• Methods: Cells are exposed to KU-60019 for 1, 3, and 5 days. Cell growth is determined by AlamarBlue. AlamarBlue is added to the medium to the recommended final concentration. Plates are incubated for 1 hour at 37 °C, fluorescence is determined on a Fluoro-Count plate reader (excitation 530 nm, emission 590 nm), and values are taken as a measure of cell growth. Cell survival is determined by trypan blue/fluorescence activated cell sorting (FACS) assay.

References

• References: [1] Golding SE, et al. Mol Cancer Ther, 2009, 8(10), 2894-2902.

REFERENCES

• Golding SE, et al. Mol Cancer Ther, 2009, 8(10), 2894-2902.