PHA-680632 - CAS 398493-79-3
Catalog number: 398493-79-3
Category: Inhibitor
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Aurora Kinase
PHA-680632 is a is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM. PHA-680632 is also the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic.
PHA-680632; PHA 680632; PHA680632.
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1.Enhancement of radiation response by inhibition of Aurora-A kinase using siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells.
Tao Y1, Zhang P, Frascogna V, Lecluse Y, Auperin A, Bourhis J, Deutsch E. Br J Cancer. 2007 Dec 17;97(12):1664-72. Epub 2007 Nov 20.
Overexpression of Aurora-A kinase has been correlated with cancer susceptibility and poor prognosis in several human cancers. In this study, we evaluated the effect of inhibition of Aurora-A kinase on cell cycle progression and tumour cell survival after exposure to ionising radiation (IR). Combined IR and Aurora-A inhibition by short interfering RNA (siRNA) or by PHA680632 (a selective Aurora kinase inhibitor with submicromolar activity against Aurora-A) prior to IR led to an enhancement of radiation-induced annexin V positive cells, micronuclei formation, and Brca1 foci formation only in cells with deficient p53. However, the drug brought about additive to sub-additive interaction with radiation with regard to in vitro clonogenic survival. Cell cycle analysis revealed a high >4N DNA content 24 h after PHA680632 exposure. DNA content >4N was reduced dramatically when cells were irradiated combined with PHA680632 simultaneously. In vivo xenografts (p53-/- HCT116) of a mice study showed enhanced tumour growth delay (TGD) after the PHA680632-IR combinatorial treatment compared with IR alone.
2.Aurora and IKK kinases cooperatively interact to protect multiple myeloma cells from Apo2L/TRAIL.
Mazzera L1, Lombardi G, Abeltino M, Ricca M, Donofrio G, Giuliani N, Cantoni AM, Corradi A, Bonati A, Lunghi P. Blood. 2013 Oct 10;122(15):2641-53. doi: 10.1182/blood-2013-02-482356. Epub 2013 Aug 23.
Constitutive activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathways is frequent in multiple myeloma (MM) and can compromise sensitivity to TRAIL. In this study, we demonstrate that Aurora kinases physically and functionally interact with the key regulators of canonical and noncanonical NF-κB pathways IκB kinase β (IKKβ) and IKKα to activate NF-κB in MM, and the pharmacological blockade of Aurora kinase activity induces TRAIL sensitization in MM because it abrogates TRAIL-induced activation of NF-κB. We specifically found that TRAIL induces prosurvival signaling by increasing the phosphorylation state of both Aurora and IKK kinases and their physical interactions, and the blockade of Aurora kinase activity by pan-Aurora kinase inhibitors (pan-AKIs) disrupts TRAIL-induced survival signaling by effectively reducing Aurora-IKK kinase interactions and NF-κB activation. Pan-AKIs consistently blocked TRAIL induction of the antiapoptotic NF-κB target genes A1/Bfl-1 and/or Mcl-1, both important targets for TRAIL sensitization in MM cells.
3.PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity.
Soncini C1, Carpinelli P, Gianellini L, Fancelli D, Vianello P, Rusconi L, Storici P, Zugnoni P, Pesenti E, Croci V, Ceruti R, Giorgini ML, Cappella P, Ballinari D, Sola F, Varasi M, Bravo R, Moll J. Clin Cancer Res. 2006 Jul 1;12(13):4080-9.
PURPOSE: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy.
4.Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death.
Ratushny V1, Pathak HB, Beeharry N, Tikhmyanova N, Xiao F, Li T, Litwin S, Connolly DC, Yen TJ, Weiner LM, Godwin AK, Golemis EA. Oncogene. 2012 Mar 8;31(10):1217-27. doi: 10.1038/onc.2011.314. Epub 2011 Jul 25.
Increased activity of SRC family kinases promotes tumor invasion and metastasis, and overexpression of the mitotic regulator Aurora kinase A (AURKA) drives tumor aneuploidy and chromosomal instability. These functions nominate SRC and AURKA as valuable therapeutic targets for cancer, and inhibitors for SRC and Aurora kinases are now being used in the clinic. In this study, we demonstrate potent synergy between multiple inhibitors of Aurora and SRC kinases in ovarian and colorectal cancer cell lines, but not in normal ovarian epithelial cell lines. Combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations. Combined inhibition of Aurora kinase and SRC potentiated dasatinib-dependent loss of activated (Y(416)-phosphorylated) SRC. SRC and AURKA share a common interaction partner, NEDD9, which serves as a scaffolding protein with activities in cell attachment and mitotic control, suggesting SRC and AURKA might interact directly.
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CAS 398493-79-3 PHA-680632

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