Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

Moore, Andrew S.; Blagg, Julian; Linardopoulos, Spiros; Pearson, Andrew D.J.

doi:10.1038/leu.2010.15

Cited by 81 publications

(59 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in FLT3 are associated with AML (42), suggesting that TAK-901 may have therapeutic potential in Flt-mutated AML (43). Tumors may only be partially sensitive to single-agent therapies, requiring interdiction of multiple protein kinases and other protein signaling targets for optimal anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

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

Farrell

Shi

Matuszkiewicz

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Farrell

Shi

Matuszkiewicz

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Additionally, it reversed the sensitivity to imatinib of T315I-mutated CML cells in comparizon to treatment only with imatinib. Recently, Aurora inhibitors were indicated as promising agents for acute myeloid and chronic myeloid leukemias (Moore et al, 2010). The most promising data was obtained for FLT3-mutated AML and imatinib-resistant Ph+ CML, particularly with the T315I mutation.…”

Section: Chromosomal Passenger Complex and Aurora Kinasesmentioning

confidence: 90%

BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

Piwocka¹,

Wolanin²,

Kusio-Kobiałka³

et al. 2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

View full text Add to dashboard Cite

“…In this trial, objective responses have been reported in some patients, including patients with T315I. The effect of the pan-Aurora, Abl, FLT3 and JAK2 inhibitor AT9283 has been also reported against CML patients who were refractory to IM and dasatinib [74]. The final results of those trials are awaited.…”

Section: The Fight Against T315imentioning

confidence: 95%

“…A phase II study of ponatinib (Ponatinib Ph+ acute lymphoblastic leukemia (ALL) and CML Evaluation or PACE) is currently under way. Moreover, several other agents, such as DCC-2036, a switch pocket inhibitor [73], or danusertib (PHA-739358), XL-228 and AT-9283, aurora kinase inhibitors, are being developed as potent therapeutics for IM/SGI-refractory CML, including patients with T315I Abl KD mutation [7,74]. Danusertib is a pan Aurora and Abl inhibitor and has been evaluated in a Phase I study for 12 advanced phase CML and 11 Ph 1 -positive ALL patients, including 15 with T315I mutation.…”

Section: The Fight Against T315imentioning

confidence: 99%

Principles and Current Topics Concerning Management of Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia

Kuroda

2013

Transl Med

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder with leukemic cells featuring the Philadelphia (Ph1) chromosome comprising the reciprocal chromosomal translocation t(9;22)(q34;q22) and the resultant constitutive active Bcr-Abl tyrosine kinase (TK). The introduction of disease-specific molecular targeted agents, that is, TK inhibitors (TKIs) for Bcr-Abl TK, such as the first-in-class TKI imatinib mesylate (IM) or the secondgeneration TKIs (SGIs) nilotinib and dasatinib, has dramatically improved the long-term treatment outcome for CML in this century. In addition, several new SGIs, such as bosutinib or bafetinib, are under development, while ponatinib, which is active against CML refractory for all preceding TKIs, for example, CML with T315I Abl kinase domain mutation, is currently being evaluated in clinical trials. Because those TKIs have different sensitivity for BcrAbl mutation and profiles for adverse effects, a thorough understanding of the pharmacologic characteristics of TKIs is mandatory for their safe and effective clinical use. Recent studies have clearly shown the faster and deeper responses to SGIs, both nilotinib and dasatinib, compared with those to IM, indicating the need for a paradigm shift in approaches to TKI therapy for treatment-naïve CML. In addition, evidence accumulated during the past decade has indicated optimal methodologies for monitoring the treatment effect of TKIs, selecting the appropriate therapeutic strategies, and predicting the outcome for treatment with TKIs for individual patients with CML. In this article, we review the principles and current knowledge and topics of the various uses of TKIs for CML. We also touch upon the reason why the faster and the deeper responses to TKIs is the prerequisite for their safer use and longer-lasting positive treatment outcome for CML.

show abstract

Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

Cited by 81 publications

References 46 publications

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

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

BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

Principles and Current Topics Concerning Management of Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia

Contact Info

Product

Resources

About