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    Abstract C202: Targeting the mitotic checkpoint for cancer therapy with NMS-P715, a novel MPS1 kinase inhibitor
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. C202-C202
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C202-C202
    Abstract: The Spindle Assembly Checkpoint (SAC) is a mitotic mechanism specifically required for proper chromosomal segregation ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. MPS1 kinase, (also known as TTK) is a key regulator of SAC functions and it has been found to be up-regulated in a number of tumors of different origins. The hypothesis is that SAC activity could be highly required to sustain aneuploid tumor growth and MPS1 inhibitors may have a therapeutic benefit in the treatment of certain cancers. We have identified NMS-P715, a potent and selective oral bioavailable small-molecule MPS1 kinase inhibitor with an ATP-competitive bindingmode. Treatment of cells with NMS-P715 accelerates mitotic exit with an IC50 of 53 nM. This is accompanied by reduction of the mitotic length, MPS1 dephosphorylation, chromosomal mis-alignment, delocalization of kinetochore components and massive aneuploidization, which ultimately leads to cell death. Proliferation data performed on a large panel of 126 cell lines shows a wide range of activity and indicates selective activity against tumoral cells compared to normal cells. Oral administration of NMS-P715 in tumor xenografted mice resulted in potent tumor growth inhibition in an ovarian cancer xenograft model and was accompanied by biomarker modulation, confirming the expected MOA. Our data provide evidence that inhibition of MPS1 kinase and SAC abrogation could represent a new promising approach to cancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C202.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-C202
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 2
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    NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies
    American Association for Cancer Research (AACR) ; 2012
    In:  Molecular Cancer Therapeutics Vol. 11, No. 4 ( 2012-04-01), p. 1006-1016
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    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 11, No. 4 ( 2012-04-01), p. 1006-1016
    Abstract: Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings. Mol Cancer Ther; 11(4); 1006–16. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-11-0765
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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