9-cyclopentyl-2-({2-methoxy-4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-7-methyl-8,9-dihydro-7H-purin-8-one

• ChemBase ID: 73196
• Molecular Formular: C24H32N6O3
• Molecular Mass: 452.54928
• Monoisotopic Mass: 452.25358891
• SMILES: c1(cc(c(cc1)Nc1nc2c(cn1)n(c(=O)n2C1CCCC1)C)OC)OC1CCN(CC1)C
• Canonical SMILES: COc1cc(ccc1Nc1ncc2c(n1)n(C1CCCC1)c(=O)n2C)OC1CCN(CC1)C
• InChI: InChI=1S/C24H32N6O3/c1-28-12-10-17(11-13-28)33-18-8-9-19(21(14-18)32-3)26-23-25-15-20-22(27-23)30(24(31)29(20)2)16-6-4-5-7-16/h8-9,14-17H,4-7,10-13H2,1-3H3,(H,25,26,27)
• InChIKey: YUKWVHPTFRQHMF-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 9-cyclopentyl-2-({2-methoxy-4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-7-methyl-8,9-dihydro-7H-purin-8-one
• IUPAC Traditional name: 9-cyclopentyl-2-({2-methoxy-4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-7-methylpurin-8-one
• Synonyms: AZ 3146

Database IDs

• CAS Number: 1124329-14-1
• PubChem SID: 162038116
• PubChem CID: 56973724

CALCULATED PROPERTIES

• Acid pKa: 12.24688
• H Acceptors: 7
• H Donor: 1
• LogD (pH = 5.5): 0.13975327
• LogD (pH = 7.4): 1.8716863
• Log P: 3.0912325
• Molar Refractivity: 126.4273 cm^3
• Polarizability: 48.085915 Å^3
• Polar Surface Area: 83.06 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: Ksp

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2731

Research Area

• Description: Cancer

Biological Activity

• Description: AZ3146 is a selective Mps1 inhibitor with IC50 of ~35 nM.
• Targets: Mps1
• IC50: ~35 nM ^[1]
• In Vitro: AZ3146 also inhibits FAK, JNK1, JNK2 and Kit. AZ3146 significantly inhibits phosphorylation of Mps1 in cells. Mitotic-specific phospho forms of aurora B and BubR1 are not affected by AZ3146. AZ3146 does not inhibit Cdk1 or aurora B in mitotic cells. HeLa cells treated with nocodazole and 2 μM AZ3146 only delay mitosis briefly and then rereplicate their genomes, indicating that AZ3146 overrides the SAC. AZ3146 also inhibits an already established SAC signal, as after release from a nocodazole block, AZ3146 dramatically accelerates mitotic exit.During an otherwise unperturbed mitosis, AZ3146 reduces the time to complete mitosis from 90 minutes in controls to 32 minutes. Strikingly, ~90% of AZ3146-treated HeLa cells undergo abnormal mitoses, although ~50% enter anaphase without aligning all of their chromosomes, and ~30% exit mitosis without undergoing obvious chromosome segregation. AZ3146 has a dramatic effect on kinetochore localization of Mad2, reducing its levels to ~15%, but its effect on Mad1 is less pronounced, with levels remaining at ~60%. When Mps1 is inhibited by AZ3146 before mitotic entry, subsequent recruitment of Mad1 and Mad2 to kinetochores is abolished. However, if Mps1 is inhibited by AZ3146 after mitotic entry, the Mad1–C-Mad2 core complex remains kinetochore bound, but O-Mad2 is not recruited to the core. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro kinase assays: For kinase assays, 500 ng His-tagged human Mps1Cat encoding amino acids 510-857 is added to buffer (25 mM Tris-HCl, pH 7.4, 100 mM NaCl, 50 μg/mL BSA, 0.1 mM EGTA, 0.1% β-mercaptoethanol, 10 mM MgCl₂, and 0.5 μg/mL myelin basic protein), AZ3146, and 100 μM γ-[^32P]ATP (2 μCi/assay). Reactions are incubated at 30°C for 20 minutes, spotted onto P81 paper, washed in 0.5% phosphoric acid, and immersed in acetone. Phosphate incorporation is determined by scintillation counting.

References

• References: [1] Hewitt L, et al. J Cell Biol, 2010, 190(1), 25-34.

REFERENCES

• Hewitt L, et al. J Cell Biol, 2010, 190(1), 25-34.