4-{[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino}benzene-1-sulfonamide

• ChemBase ID: 72592
• Molecular Formular: C15H12F2N6O3S
• Molecular Mass: 394.3559864
• Monoisotopic Mass: 394.06596571
• SMILES: c1(ccc(cc1)Nc1nc(n(n1)C(=O)c1c(cccc1F)F)N)S(=O)(=O)N
• Canonical SMILES: Fc1cccc(c1C(=O)n1nc(nc1N)Nc1ccc(cc1)S(=O)(=O)N)F
• InChI: InChI=1S/C15H12F2N6O3S/c16-10-2-1-3-11(17)12(10)13(24)23-14(18)21-15(22-23)20-8-4-6-9(7-5-8)27(19,25)26/h1-7H,(H2,19,25,26)(H3,18,20,21,22)
• InChIKey: KDKUVYLMPJIGKA-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-{[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino}benzene-1-sulfonamide
• IUPAC Traditional name: 4-{[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino}benzenesulfonamide
• Synonyms: JNJ-7706621

Database IDs

• CAS Number: 443797-96-4
• PubChem SID: 162037517
• PubChem CID: 5330790

CALCULATED PROPERTIES

• Acid pKa: 10.268462
• H Acceptors: 7
• H Donor: 3
• LogD (pH = 5.5): 2.280357
• LogD (pH = 7.4): 2.2798111
• Log P: 2.2803643
• Molar Refractivity: 94.0569 cm^3
• Polarizability: 34.494225 Å^3
• Polar Surface Area: 145.99 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; CDK

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1249

Research Area

• Description: Cancer

Biological Activity

• Description: JNJ-7706621 is a potent and multi-target inhibitor for CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, Aurora A and Aurora B with IC50 of 9 nM, 4 nM, 3 nM, 11 nM and 15 nM, respectively.
• Targets: CDK1/Cyclin B; CDK2/Cyclin A; CDK2/Cyclin E; Aurora-A; Aurora-B
• IC50: 9 nM; 4 nM; 3 nM; 11 nM; 15 nM ^[1]
• In Vitro: JNJ-7706621 also shows some inhibition to VEGF-R2, FGF-R2, and GSK3β, with IC50 of 154–254 nM. JNJ-7706621 shows inhibitory effect on a panel of human cancer cell types, including HeLa, HCT-116, SK-OV-3, PC3, DU145, A375, MDA-MB-231, MES-SA, and MES-SA/Dx5, with IC50 of 112–514 nM, independent of p53, retinoblastoma, or P-glycoprotein status. JNJ-7706621 is several-fold less potent at inhibiting growth of normal cell types, including MRC-5, HASMC, HUVEC, and HMVEC, with IC50 of 3.67–5.42 μM. In HeLa or U937 cells, JNJ-7706621 (0.5–3 μM) delays exit from G1, arrests cells in G2-M, induces endoreduplication, activates apoptosis, and reduces colony formation. ^[1] In a HeLa cell line, incremental treatment with increasing concentrations of JNJ-7706621 leads to a 16-fold resistance, which may be mediated by ABCG2. ^[2]
• In Vivo: In mouse xenograft model of A375 melanoma human tumor, JNJ-7706621 (100 or 125 mg/kg) causes tumor regression. ^[3]
• Features: JNJ-7706621 is a broad-spectrum inhibitor.

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro kinase assay for CDK1 and Aurora kinases: For CDK1 kinase activity, a method is developed using the CDK1/cyclin B complex purified from baculovirus to phosphorylate a biotinylated peptide substrate containing the consensus phosphorylation site for histone H1, which is phosphorylated in vivo by CDK1. Inhibition of CDK1 activity is measured by observing a reduced amount of ^33P-γ-ATP incorporation into the immobilized substrate in streptavidin-coated 96-well scintillating microplates. CDK1 enzyme is diluted in 50 mM Tris-HCl (pH 8), 10 mM MgCl₂, 0.1 mM Na₃VO ₄, 1 mM DTT, 1% DMSO, 0.25 μM peptide, 0.1 μCi per well ^33P-γ-ATP, and 5 μM ATP in the presence or absence of various concentrations of JNJ-7706621 and incubated at 30 °C for 1 hour. The reaction is terminated by washing with PBS containing 100 mM EDTA and plates are counted in a scintillation counter. Linear regression analysis of the percent inhibition by JNJ-7706621 is used to determine IC50. The Aurora kinase assays are done with 10 μM ATP and a peptide containing a dual repeat of the kemptide phosphorylation motif.
• Protocol: Cell Assay ^[3]
• Cell Lines: HeLa, HCT-116, A375, SK-OV-3, MDA-MB-231, and PC-3 cells
• Concentrations: 1 nM - 10 μM, dissolved in DMSO
• Incubation Time: 48 hours
• Methods: The ability of JNJ-7706621 to inhibit the proliferation of cell growth is determined by measuring incorporation of ^14C-labelled thymidine into newly synthesized DNA within the cells. Cells are trypsinized and counted and 3-8 × 10^3 cells are added to each well of a 96-well CytoStar tissue culture treated scintillating microplate in complete medium in a volume of 100 μL. Cells are incubated for 24 hours in complete medium at 37 °C in an atmosphere containing 5% CO₂. Next, 1 μL of JNJ-7706621 is added to the wells of the plate. Cells are incubated for 24 more hours. Methyl ^14C-thymidine 56 mCi/mmol is diluted in complete medium and 0.2 μCi/well is added to each well of the CytoStar plate in a volume of 20 μL. The plate is incubated for 24 hours at 37 °C in JNJ-7706621 plus ^14C-thymidine. The contents of the plate are discarded and the plate is washed twice with 200 μL PBS. 200 μL of PBS is added to each well. The top of the plate is sealed with a transparent plate sealer and a white plate backing sealer is applied to the bottom of the plate. The degree of methyl ^14C-thymidine incorporation is quantified on a Packard Top Count.
• Protocol: Animal Study ^[1]
• Animal Models: Mouse xenograft model of A375 cells
• Formulation: Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
• Doses: 100 or 125 mg/kg
• Administration: Orally or by intraperitoneal injection injection

References

• References: [1] Emanuel S, et al. Cancer Res, 2005, 65(19), 9038-9046.
• References: [2] Seamon JA, et al. Mol Cancer Ther, 2006, 5(10), 2459-2467.
• References: [3] Lin R, et al. J Med Chem, 2005, 48(13), 4208-4211.

REFERENCES

• Emanuel S, et al. Cancer Res, 2005, 65(19), 9038-9046.
• Seamon JA, et al. Mol Cancer Ther, 2006, 5(10), 2459-2467.
• Lin R, et al. J Med Chem, 2005, 48(13), 4208-4211.