dc.contributor.author | Osborne, JD | |
dc.contributor.author | Matthews, TP | |
dc.contributor.author | McHardy, T | |
dc.contributor.author | Proisy, N | |
dc.contributor.author | Cheung, K-MJ | |
dc.contributor.author | Lainchbury, M | |
dc.contributor.author | Brown, N | |
dc.contributor.author | Walton, MI | |
dc.contributor.author | Eve, PD | |
dc.contributor.author | Boxall, KJ | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Valenti, MR | |
dc.contributor.author | De Haven Brandon, AK | |
dc.contributor.author | Box, G | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Westwood, IM | |
dc.contributor.author | van Montfort, RLM | |
dc.contributor.author | Leonard, PM | |
dc.contributor.author | Lamers, MBAC | |
dc.contributor.author | Reader, JC | |
dc.contributor.author | Aherne, GW | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Garrett, MD | |
dc.contributor.author | Collins, I | |
dc.date.accessioned | 2016-08-16T14:27:06Z | |
dc.date.issued | 2016-06-09 | |
dc.identifier.citation | Journal of medicinal chemistry, 2016, 59 (11), pp. 5221 - 5237 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/46 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.5b01938 | |
dc.description.abstract | Multiparameter 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.format | Print-Electronic | |
dc.format.extent | 5221 - 5237 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | 4-Aminopyridine | |
dc.subject | Pyrazines | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Molecular Structure | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Models, Molecular | |
dc.subject | Checkpoint Kinase 1 | |
dc.title | Multiparameter 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.type | Journal Article | |
dcterms.dateAccepted | 2016-05-10 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.5b01938 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 11 | |
pubs.notes | No 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-status | Published | |
pubs.volume | 59 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Medicinal Chemistry 2 | |
icr.researchteam | Pre-Clinical MRI | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Matthews, Thomas | |
dc.contributor.icrauthor | McHardy, Tatiana | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Collins, Ian | |