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dc.contributor.authorOsborne, JD
dc.contributor.authorMatthews, TP
dc.contributor.authorMcHardy, T
dc.contributor.authorProisy, N
dc.contributor.authorCheung, K-MJ
dc.contributor.authorLainchbury, M
dc.contributor.authorBrown, N
dc.contributor.authorWalton, MI
dc.contributor.authorEve, PD
dc.contributor.authorBoxall, KJ
dc.contributor.authorHayes, A
dc.contributor.authorHenley, AT
dc.contributor.authorValenti, MR
dc.contributor.authorDe Haven Brandon, AK
dc.contributor.authorBox, G
dc.contributor.authorJamin, Y
dc.contributor.authorRobinson, SP
dc.contributor.authorWestwood, IM
dc.contributor.authorvan Montfort, RLM
dc.contributor.authorLeonard, PM
dc.contributor.authorLamers, MBAC
dc.contributor.authorReader, JC
dc.contributor.authorAherne, GW
dc.contributor.authorRaynaud, FI
dc.contributor.authorEccles, SA
dc.contributor.authorGarrett, MD
dc.contributor.authorCollins, I
dc.date.accessioned2016-08-16T14:27:06Z
dc.date.issued2016-06
dc.identifier.citationJournal of medicinal chemistry, 2016, 59 (11), pp. 5221 - 5237
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/46
dc.identifier.eissn1520-4804
dc.identifier.doi10.1021/acs.jmedchem.5b01938
dc.description.abstractMultiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.
dc.formatPrint-Electronic
dc.format.extent5221 - 5237
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subject4-Aminopyridine
dc.subjectPyrazines
dc.subjectProtein Kinase Inhibitors
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectDose-Response Relationship, Drug
dc.subjectModels, Molecular
dc.subjectCheckpoint Kinase 1
dc.titleMultiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
dc.typeJournal Article
dcterms.dateAccepted2016-05-10
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1021/acs.jmedchem.5b01938
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of medicinal chemistry
pubs.issue11
pubs.notesNo embargo
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/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 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI
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/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 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI
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.volume59
pubs.embargo.termsNo embargo
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamPre-Clinical MRIen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorMcHardy, Tatianaen
dc.contributor.icrauthorBrown, Nathanen
dc.contributor.icrauthorVan Montfort, Roberten
dc.contributor.icrauthorJamin, Yannen
dc.contributor.icrauthorCollins, Ianen
dc.contributor.icrauthorRobinson, Simonen


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