4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl]pyrimidin-2-amine

• ChemBase ID: 72555
• Molecular Formular: C18H20N6OS
• Molecular Mass: 368.456
• Monoisotopic Mass: 368.14193029
• SMILES: c1(nccc(n1)c1sc(nc1C)N)Nc1ccc(cc1)N1CCOCC1
• Canonical SMILES: Nc1nc(c(s1)c1ccnc(n1)Nc1ccc(cc1)N1CCOCC1)C
• InChI: InChI=1S/C18H20N6OS/c1-12-16(26-17(19)21-12)15-6-7-20-18(23-15)22-13-2-4-14(5-3-13)24-8-10-25-11-9-24/h2-7H,8-11H2,1H3,(H2,19,21)(H,20,22,23)
• InChIKey: GPSZYOIFQZPWEJ-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl]pyrimidin-2-amine
• IUPAC Traditional name: 4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl]pyrimidin-2-amine
• Synonyms: CYC116

Database IDs

• CAS Number: 693228-63-6
• PubChem SID: 162037480
• PubChem CID: 6420138

CALCULATED PROPERTIES

• Acid pKa: 14.530921
• H Acceptors: 7
• H Donor: 2
• LogD (pH = 5.5): 2.7175517
• LogD (pH = 7.4): 2.733058
• Log P: 2.7332594
• Molar Refractivity: 103.1795 cm^3
• Polarizability: 39.3641 Å^3
• Polar Surface Area: 89.19 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: Aurora Kinase; VEGFR

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1171

Research Area

• Description: Cancer

Biological Activity

• Description: CYC116 is a potent inhibitor of Aurora A and Aurora B with K_i of 8.0 nM and 9.2 nM, respectively.
• Targets:

  Aurora A

  ;

  Aurora B

• IC50:

  8.0 nM (K_i)

  ;

  9.2 nM (K_i) ^[1]

• In Vitro: The most Aurora-selective CYC116 shows inhibitory effect on Aurora A and B kinases 50-fold more potently than any of the CDKs assayed. ^[1] CYC116 is initially screened against a panel of human leukemia and solid tumor cell lines using an MTT antiproliferative assay. The results show that CYC116 has broad-spectrum antitumor activity and shows specific cytotoxicity against the acute myelogenous leukemia cell line MV4-11 with IC50 of 34 nM. ^[1] In addition, anti-proliferative activity of CYC116 is found to be associated with Aurora A and B modulation such as, inhibition of Aurora autophosphorylation, reduction of histone H3 phosphorylation, polyploidy, followed by cell death, resulting from a failure in cytokinesis. ^[1]
• In Vivo: Mice bearing subcutaneous NCI-H460 xenografts are given CYC116 orally for 5 days, at dose levels of 75 and 100 mg/kg q.d. It leads to tumor growth delays of 2.3 and 5.8 days, which translated into specific growth delays of 0.32 and 0.81, respectively. ^[1]
• Clinical Trials: CYC116 is currently being investigated in Phase I clinical trials in patients with advanced solid tumors.
• Features: CYC116 is an orally bioavailable, small molecule; an inhibitor of Aurora kinase/VEGFR2.

Protocol

• Protocol: Kinase Assay ^[1]
• Kinase Assays: Aurora A kinase assays are performed using a 25 μL reaction volume (25 mM β-glycerophosphate, 20 mM Tris/HCl, pH 7.5, 5 mM EGTA, 1 mM DTT, 1 mM Na₃VO₄, 10 μg of kemptide (peptide substrate)). Recombinant Aurora A kinase is diluted in 20 mM Tris/HCl, pH 8, containing 0.5 mg/mL BSA, 2.5% glycerol, and 0.006% Brij-35. Reactions are started by the addition of 5 μL Mg/ATP mix (15 mM MgCl₂, 100 μM ATP, with 18.5 kBq γ-^32P-ATP per well) and incubated at 30°C for 30 minutes before termination with 25 μL of 75 mM H₃PO₄. Aurora B kinase assays are performed like Aurora A except that prior to use, Aurora B is activated in a separate reaction at 30°C for 60 minutes with inner centromere protein.
• Protocol: Cell Assay ^[1]
• Cell Lines: HeLa, MCF7, MV4-11 and A2780 cells
• Concentrations: 0-10 μM
• Incubation Time: 72 or 96 hours
• Methods:

  Standard MTT assays are performed. In short, cells are seeded into 96-well plates according to doubling time and incubated overnight at 37°C. Test compounds are made up in DMSO, a 3-fold dilution series is prepared in 100 μL of cell medium, added to cells (in triplicates) and incubated for 72 or 96 hours at 37°C. MTT is made up as a stock of 5 mg/mL in cell medium, and the solution is filter-sterilized. Medium is removed from the cells followed by a wash with PBS. MTT solution is then added at 20 μL/well and incubated in the dark at 37°C for 4 hours. MTT solution is removed and cells are again washed with 200 μL of PBS. MTT dye is solubilized with 200 μL/well of DMSO by agitation. Absorbance is read at 540 nm and data analyzed using curve-fitting software to determine IC50 values.

• Protocol: Animal Study ^[1]
• Animal Models: NCI-H460 cells are implanted intraperitoneally into the mice.
• Formulation: CYC116 is dissolved in DMSO and then diluted in water.
• Doses: 75 and 100 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Wang S, et al. J Med Chem. 2010, 53(11), 4367-4378.

REFERENCES

• Wang S, et al. J Med Chem. 2010, 53(11), 4367-4378.