Aurora kinase inhibitors in preclinical and clinical testing

Cheung, Chun Hei Antonio; Coumar, Mohane Selvaraj; Hsieh, Hsing Pang; Chang, Jang Yang

doi:10.1517/13543780902806392

Cited by 98 publications

(66 citation statements)

References 93 publications

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“…1). Finally, Aurora-A inhibitors are currently used in clinical trials (37). Our findings indicate that inhibition of Aurora-A or the combination with other therapeutic modalities could have great potential to overcome hormone-refractory prostate cancer.…”

Section: Discussionmentioning

confidence: 80%

Phosphorylation and Activation of Androgen Receptor by Aurora-A

Shu

Liu

Coppola

et al. 2010

Journal of Biological Chemistry

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Aurora-A kinase is frequently overexpressed/activated in various types of human malignancy, including prostate cancer. In this study, we demonstrate elevated levels of Aurora-A in androgen-refractory LNCaP-RF but not androgen-sensitive LNCaP cells, which prompted us to examine whether Aurora-A regulates the androgen receptor (AR) and whether elevated Aurora-A is involved in androgen-independent cell growth. We show that ectopic expression of Aurora-A induces AR transactivation activity in the presence and absence of androgen. Aurora-A interacts with AR and phosphorylates AR at Thr 282 and Ser 293 in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner. Ectopic expression of Aurora-A in LNCaP cells induces prostate-specific antigen expression and cell survival, whereas knockdown of Aurora-A sensitizes LNCaP-RF cells to apoptosis and cell growth arrest. These data indicate that AR is a substrate of Aurora-A and that elevated Aurora-A could contribute to androgen-independent cell growth by phosphorylation and activation of AR.

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Section: Discussionmentioning

confidence: 80%

Phosphorylation and Activation of Androgen Receptor by Aurora-A

Shu

Liu

Coppola

et al. 2010

Journal of Biological Chemistry

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“…To date, no dose-limiting toxicities have been observed and dose escalation is ongoing. 5 These chronic exposures would not be anticipated to be safely achieved with potent Aurora inhibitor molecules from previously reported data for this class of mitotic inhibitor (37). Thus, there is an apparent disconnect between the biochemical data of BMS-754807 for Aurora kinase activity.…”

Section: Discussionmentioning

confidence: 99%

BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Carboni

Wittman

Yang

et al. 2009

Molecular Cancer Therapeutics

244

214

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BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC 50 , 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G 1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.

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“…In vitro studies suggest that elevated Aurora A may promote oncogenesis (14,15), and its overexpression is associated with chromosome instability and clinically aggressive disease (5,15,16). Elevated expression of Aurora B has also been seen in multiple human tumors and cancer cell lines and correlates with disease severity and a poor prognosis (11,12,15,(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…However, many pan-Aurora kinase inhibitors generate a similar polyploid cellular phenotype, which is a hallmark of Aurora B inactivation (11,14). More than 10 small-molecule inhibitors have entered early clinical development, including selective inhibitors of Aurora A (23)(24)(25), B, or C (26)(27)(28)(29) and panAurora kinase inhibitors (30)(31)(32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

Farrell

Shi

Matuszkiewicz

et al. 2013

Molecular Cancer Therapeutics

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Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers. Mol Cancer Ther; 12(4); 460-70. Ó2013 AACR.

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Aurora kinase inhibitors in preclinical and clinical testing

Cited by 98 publications

References 93 publications

Phosphorylation and Activation of Androgen Receptor by Aurora-A

Phosphorylation and Activation of Androgen Receptor by Aurora-A

BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

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