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dc.contributor.authorFaisal, A
dc.contributor.authorMak, GWY
dc.contributor.authorGurden, MD
dc.contributor.authorXavier, CPR
dc.contributor.authorAnderhub, SJ
dc.contributor.authorInnocenti, P
dc.contributor.authorWestwood, IM
dc.contributor.authorNaud, S
dc.contributor.authorHayes, A
dc.contributor.authorBox, G
dc.contributor.authorValenti, MR
dc.contributor.authorDe Haven Brandon, AK
dc.contributor.authorO'Fee, L
dc.contributor.authorSchmitt, J
dc.contributor.authorWoodward, HL
dc.contributor.authorBurke, R
dc.contributor.authorvanMontfort, RLM
dc.contributor.authorBlagg, J
dc.contributor.authorRaynaud, FI
dc.contributor.authorEccles, SA
dc.contributor.authorHoelder, S
dc.contributor.authorLinardopoulos, S
dc.date.accessioned2017-04-11T14:16:15Z
dc.date.issued2017-04
dc.identifier.citationBritish journal of cancer, 2017, 116 (9), pp. 1166 - 1176
dc.identifier.issn0007-0920
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/582
dc.identifier.eissn1532-1827
dc.identifier.doi10.1038/bjc.2017.75
dc.description.abstractBackground 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.Methods 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.Results 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.Conclusions 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.
dc.formatPrint-Electronic
dc.format.extent1166 - 1176
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHCT116 Cells
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectNeoplasms
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectCell Cycle Proteins
dc.subjectProtein Kinase Inhibitors
dc.subjectXenograft Model Antitumor Assays
dc.subjectProtein-Tyrosine Kinases
dc.subjectM Phase Cell Cycle Checkpoints
dc.subjectHeterocyclic Compounds, 4 or More Rings
dc.titleCharacterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.
dc.typeJournal Article
dcterms.dateAccepted2017-03-01
rioxxterms.versionofrecord10.1038/bjc.2017.75
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBritish journal of cancer
pubs.issue9
pubs.notesNot known
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.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-statusPublished
pubs.volume116
pubs.embargo.termsNot known
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.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorHoelder, Swenen
dc.contributor.icrauthorVan Montfort, Roberten


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