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In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465.

ABSTRACT: This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), doxorubicin (Doxo) and bortezomib showed no antagonism. Our study highlights the potential role of the tumour microenvironment in modulating the activity of this drug class.

SUBMITTER: Negri JM

PROVIDER: S-EPMC3672411 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465.

Negri Joseph M JM McMillin Douglas W DW Delmore Jake J Mitsiades Nicholas N Hayden Patrick P Klippel Steffen S Hideshima Teru T Chauhan Dharminder D Munshi Nikhil C NC Buser Carolyn A CA Pollard John J Richardson Paul G PG Anderson Kenneth C KC Mitsiades Constantine S CS

British journal of haematology 20090914 5

This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), do ...[more]

PMID: 19751238

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Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity.

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Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition.

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Human ALL Cell line RS4;11: Control vs. VE-465 treated

Project description:Transcriptional profiling of human acute lymphoblastic leukemia cell lines RS4;11: compare untreated RS4;11 with RS4;11 treated with VE-465. The goal was to determine the effects of VE-465 on global gene expression in RS4;11.

2012-11-30 | GSE42620 | GEO

Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.

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| S-EPMC3549034 | biostudies-literature

Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase.

Project description:Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G(2)/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.

| S-EPMC1820716 | biostudies-literature

The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and Aurora kinases.

Project description:Background: Despite the development of several FLT3 inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemias (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways such as those regulated by BTK, aurora kinases, and potentially others in addition to acquired tyrosine kinase domains (TKD) mutations of FLT3 gene. FLT3 may not always be a driver mutation. Objective: To evaluate the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, in order to circumvent drug resistance and target FLT3 wild-type (WT) cells. Methods : The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing cell cycle with flow cytometry in vitro , and its anti-leukemia Results: CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo , regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile of FLT3, BTK, and aurora kinases. In FLT3 mutant cells, CG-806 induced G1 phase blockage, while in FLT3 WT cells, it resulted in G2/M arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously resulted in a synergistic pro-apoptotic effect in FLT3 mutant leukemia cells. Conclusion: The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemia efficacy, regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).

| S-EPMC9980215 | biostudies-literature

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