Show simple item record

dc.contributor.authorFaisal, Aen_US
dc.contributor.authorMak, GWYen_US
dc.contributor.authorGurden, MDen_US
dc.contributor.authorXavier, CPRen_US
dc.contributor.authorAnderhub, SJen_US
dc.contributor.authorInnocenti, Pen_US
dc.contributor.authorWestwood, IMen_US
dc.contributor.authorNaud, Sen_US
dc.contributor.authorHayes, Aen_US
dc.contributor.authorBox, Gen_US
dc.contributor.authorValenti, MRen_US
dc.contributor.authorDe Haven Brandon, AKen_US
dc.contributor.authorO'Fee, Len_US
dc.contributor.authorSchmitt, Jen_US
dc.contributor.authorWoodward, HLen_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorvanMontfort, RLMen_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorHoelder, Sen_US
dc.contributor.authorLinardopoulos, Sen_US
dc.date.accessioned2017-04-11T14:16:15Z
dc.date.issued2017-04en_US
dc.identifier.citationBritish journal of cancer, 2017, 116 (9), pp. 1166 - 1176en_US
dc.identifier.issn0007-0920en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/582
dc.identifier.eissn1532-1827en_US
dc.identifier.doi10.1038/bjc.2017.75en_US
dc.description.abstract<h4>Background</h4>The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers.<h4>Methods</h4>To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment.<h4>Results</h4>CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model.<h4>Conclusions</h4>CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1166 - 1176en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectHCT116 Cellsen_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectNeoplasmsen_US
dc.subjectProtein-Serine-Threonine Kinasesen_US
dc.subjectCell Cycle Proteinsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectProtein-Tyrosine Kinasesen_US
dc.subjectM Phase Cell Cycle Checkpointsen_US
dc.subjectHeterocyclic Compounds, 4 or More Ringsen_US
dc.titleCharacterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-03-01en_US
rioxxterms.versionofrecord10.1038/bjc.2017.75en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-04en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBritish journal of canceren_US
pubs.issue9en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublisheden_US
pubs.volume116en_US
pubs.embargo.termsNot knownen_US
icr.researchteamDrug Target Discoveryen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamMedicinal Chemistry 4 (including Analytical Chemistry)en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorVan Montfort, Roberten_US
dc.contributor.icrauthorLinardopoulos, Spyridonen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorHoelder, Swenen_US


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/