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PHA-680632 Aurora Kinase inhibitor

Cat.No.S1454

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. This compound has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
PHA-680632 Aurora Kinase inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 501.62

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Quality Control

Batch: Purity: 99.53%
99.53

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (199.35 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 501.62 Formula

C28H35N7O2

 Storage (From the date of receipt)
CAS No. 398493-79-3 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CCC1=C(C(=CC=C1)CC)NC(=O)N2CC3=C(C2)NN=C3NC(=O)C4=CC=C(C=C4)N5CCN(CC5)C

Mechanism of Action

Targets/IC50/Ki
Aurora A
27 nM
Aurora C
120 nM
Aurora B
135 nM
FGFR1
390 nM
PLK1
780 nM
FLT3
820 nM
VEGFR3
1000 nM
VEGFR2
1920 nM
LCK
1950 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. This compound 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 μM for another 22 kinases. It shows potent anti-proliferative effects in a wide range of cell types with IC50 values of 0.06–7.15 μM, including HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells. This chemical (0.5 μM) causes polyploidy in tumor cells. The mechanism of action of this compound is in agreement with inhibition of Aurora kinases. This compound in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of this chemical (100–400 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 wild-type counterparts.
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 γ33-ATP. The phosphorylated substrate is then captured using streptavidin-coated scintillation proximity assay beads and the extent of phosphorylation is evaluated by β-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 this compound toward Aurora kinases is evaluated and IC50 values are determined.
In vivo
HA-680632 (15–60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. This compound (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.
References

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