monastrol has been researched along with ispinesib* in 3 studies
1 review(s) available for monastrol and ispinesib
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Progress on kinesin spindle protein inhibitors as anti-cancer agents.
The kinesin spindle protein (KSP, also known as Hs Eg5) plays an essential part in the proper separation of spindle poles and the correct formation of bipolar mitotic spindle during mitosis. Inhibition of this protein results in cells apoptosis followed by mitotic arrest and the formation of characteristic monoaster spindles. Compared with the traditional chemotherapeutic agents (taxanes, vinca alkaloids), KSP inhibitors (KSPi) will not lead to the neuropathic side effects, so KSP has become a novel and an attractive anticancer target. Accordingly, more and more interest has been focused on the development of high effective and selective KSPi. This review will focus on some kinds of KSPi on the basis of introducing structure and function of KSP. Topics: Adenosine Triphosphate; Antineoplastic Agents; Benzamides; Humans; Kinesins; Models, Biological; Models, Molecular; Neoplasms; Pyrimidines; Quinazolines; Spindle Apparatus; Thiones | 2008 |
2 other study(ies) available for monastrol and ispinesib
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Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer.
An imaged-based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi-drug therapies for the treatment of triple-negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple-negative breast cancer (TNBC) was achieved by integrating high-content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA-approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule-targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib-induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image-based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers. Topics: Animals; Apoptosis; Benzamides; Cell Line, Tumor; Drug Synergism; Female; Humans; Kinesins; Mice; Mice, Inbred BALB C; Mitosis; Pyrimidines; Quinazolines; Thiones; Triple Negative Breast Neoplasms; Vinblastine; Xenograft Model Antitumor Assays | 2014 |
Thermodynamics of nucleotide and inhibitor binding to wild-type and ispinesib-resistant forms of human kinesin spindle protein.
Current antimitotic cancer chemotherapy based on vinca alkaloids and taxanes target tubulin, a protein required not only for mitotic spindle formation but also for the overall structural integrity of terminally differentiated cells. Among many innovations targeting specific mitotic events, inhibition of motor enzymes including KSP (or Eg5) has been validated as a highly productive approach. Many reported KSP inhibitors bind to an induced allosteric site near the site of ATP hydrolysis, and some have been tested in clinical trials with varying degrees of success. This allosteric site was defined in detail by X-ray crystallography of inhibitor complexes, yet complementary information on binding thermodynamics is still lacking. Using two model ATP-uncompetitive inhibitors, monastrol and ispinesib, we report here the results of thermal denaturation and isothermal titration calorimetric studies. These binding studies were conducted with the wild-type KSP motor domain as well as two ispinesib mutants (D130V and A133D) identified to confer resistance to ispinesib treatment. The thermodynamic parameters obtained were placed in the context of the available structural information and corresponding models of the two ispinesib-resistant mutants. The resulting overall information formed a strong basis for future structure-based design of inhibitors of KSP and related motor enzymes. Topics: Adenosine Diphosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Amino Acid Substitution; Benzamides; Biocatalysis; Calorimetry; Circular Dichroism; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Kinesins; Kinetics; Magnesium; Models, Molecular; Nucleotides; Protein Binding; Protein Structure, Tertiary; Pyrimidines; Quinazolines; Recombinant Fusion Proteins; Temperature; Thermodynamics; Thiones; Transition Temperature | 2009 |