Aurora proteins belong to a small family of serine/threonine kinases, including three members: Aurora A, Aurora B, and the less well characterized Aurora C, that regulate the structure and function of the cytoskeleton and chromosomes and the interactions between these two at the kinetochore. They also regulate signalling by the spindle-assembly checkpoint pathway and cytokinesis. Perturbation of Aurora kinase expression or function might lead to cancer[3]. PHA-680632 is a novel, highly selective Aurora kinase inhibitor, with three Aurora kinases with IC50s of 27, 135 and 120 nM for Aurora A, B, and C respectively, that inhibits the phosphorylation of Histone H3 in Ser10, which is mediated by Aurora B kinase. In a vitro study, C33A, HeLa, HCT116, HT29 cell lines were treated with PHA-680632 and incubated for 72 hours. It indicates that PHA-680632 is a efficient cell cycle inhibitor with IC50 values of 0.32 μM, 0.41 μM, 0.06 μM and 1.17 μM for C33A, HeLa, HCT116, HT29 cell lines respectively. In a vivo study, A2780 human ovarian carcinoma and HCT116 colon carcinoma cell lines were transplanted s.c. into athymic mice. In the A2780 human ovarian carcinoma model, the dose of 60 mg/kg i.v. b.i.d. for 5 days showed potent tumor inhibition, reaching 78% of TGI compared with the vehicle-treated controls. A more prolonged exposure to PHA-680632 was tested in the HCT116 colon carcinoma xenograft, administering the compound i.p. t.i.d. for 12 days. The treatments were also in this case well tolerated and TGI was 75% compared with controls[3].
作用机制
PHA-680632 inhibit autophosphorylation at Thr248 in the activation loop and process of binding to the CPC protein INCENP[4].
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