PHA-680632

ArtNr	S1454-5
Hersteller	Selleckchem
CAS-Nr.	398493-79-3
Menge	5 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 5 mg 50 mg 5 g
Kategorie	Oncology Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Bladder Cancer Colorectal Cancer Breast Cancer Testicular & Prostate Cancer
Typ	Inhibitors
Specific against	other
Smiles	CCC1=C(C(=CC=C1)CC)NC(=O)N2CC3=C(C2)NN=C3NC(=O)C4=CC=C(C=C4)N5CCN(CC5)C
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	Aurora A,Aurora B,Aurora C,Aurora Kinase
Similar products	PHA-680632
Lieferbar
Storage Conditions	2 years -80 in solvent
Molecular Weight	501, 62
Administration	Intraperitoneal (i.p.) injection twice a day
Animal Models	Mice (female athymic nude) xenografts models of p53 / HCT116 cells
Cell lines	HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells
Concentrations	0.001-1 uM, dissolved in DMSO as 10 mM stock solution
Dosages	40 mg/kg
Formulation	Dissolved in 20% Tween-80 in 5% glucose solution
IC50	27 nM, 27 nM, 27 nM, 27 nM, 27 nM, 27 nM
In vitro	PHA-680632 potently inhibits all three Aurora kinases (A, B, and C) with IC50 values of 27, 135, and 120 nM, respectively. PHA-680632 is selective for Aurora kinases, with 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, VEGFR2, and VEGFR3, and with IC50 higher than 10 uM for another 22 kinases. PHA-680632 shows potent anti-proliferative effects in a wide range of cell types with IC50 values of 0.06â€“7.15 uM, including HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells. PHA-680632 (0.5 uM) causes polyploidy in tumor cells. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. [1] PHA680632 in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of PHA680632 (100â€“400 nM) prior to IR leads to an enhancement of radiation-induced Annexin V positive cells, micronuclei formation, and Brca1 foci formation only in HCT116 cells with deficient p53, other than the p53 wtype counterparts. [2]
In vivo	HA-680632 (15â€“60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. PHA-680632 (45 mg/kg) suppresses growth of activated ras-driven mammary tumors in mouse mammary tumor virus v-Ha-ras transgenic mice and results in complete tumor stabilization and partial regression. [1]
Incubation Time	72 hours
Kinase Assay	Aurora Kinase Inhibition Assay, Inhibition of kinase activity by PHA-680632 is assessed using a scintillation proximity assay format. The biotinylated substrate is transphosphorylated by the kinase in presence of ATP traced with gamma33-ATP. The phosphorylated substrate is then captured using streptavidin-coated scintillation proximity assay beads and the extent of phosphorylation is evaluated by beta-counter after a 4-hour rest for the floatation of the beads on a dense 5 M CsCl solution. In particular, a peptide derived from the Chocktide sequence (LRRWSLGL) is used as substrate for Aurora A, whereas the optimized peptide Auroratide is employed for Aurora B and C. The assay is run in a robotized format on 96-well plates. The potency of the compound toward Aurora kinases is evaluated and IC50 values are determined.
Method	Cells (5x103 to 1.5x104 per cm2) are seeded in 24-well plate. After 24 hours, plates are treated with PHA-680632 and incubated for 72 hours. At the end of incubation time, cells are detached from each plate and counted using a cell counter. IC50s are calculated using percentage of growth versus untreated control.
Solubility (25C)	DMSO 100 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	PHA-680632 is a potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
Chemical Name	N-(2, 6-diethylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)pyrrolo[3, 4-c]pyrazole-5(1H, 4H, 6H)-carboxamide

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