dc.contributor.author | Walton, MI | |
dc.contributor.author | Eve, PD | |
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 | Boxall, KJ | |
dc.contributor.author | Tall, M | |
dc.contributor.author | Swales, K | |
dc.contributor.author | Matthews, TP | |
dc.contributor.author | McHardy, T | |
dc.contributor.author | Lainchbury, M | |
dc.contributor.author | Osborne, J | |
dc.contributor.author | Hunter, JE | |
dc.contributor.author | Perkins, ND | |
dc.contributor.author | Aherne, GW | |
dc.contributor.author | Reader, JC | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Collins, I | |
dc.contributor.author | Garrett, MD | |
dc.date.accessioned | 2020-06-26T09:53:15Z | |
dc.date.issued | 2016-01-19 | |
dc.identifier.citation | Oncotarget, 2016, 7 (3), pp. 2329 - 2342 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3779 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.4919 | |
dc.description.abstract | CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition. | |
dc.format | Print | |
dc.format.extent | 2329 - 2342 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | HT29 Cells | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Lymphoma, B-Cell | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lung Neoplasms | |
dc.subject | DNA Damage | |
dc.subject | 4-Aminopyridine | |
dc.subject | Camptothecin | |
dc.subject | Pyrazines | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | CDC2 Protein Kinase | |
dc.subject | Proto-Oncogene Proteins c-myc | |
dc.subject | Deoxycytidine | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Apoptosis | |
dc.subject | Drug Synergism | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Cell Cycle Checkpoints | |
dc.subject | Checkpoint Kinase 2 | |
dc.subject | Checkpoint Kinase 1 | |
dc.subject | Irinotecan | |
dc.title | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-07-11 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.4919 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 3 | |
pubs.notes | Not 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/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
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/Medicinal Chemistry 2 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
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/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
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/Medicinal Chemistry 2 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Pharmacology & Stress Response (CPSR) | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 2 | |
icr.researchteam | Tumour Biology & Metastasis | |
icr.researchteam | Clinical PD Biomarker Group | |
dc.contributor.icrauthor | Valenti, Melanie | |
dc.contributor.icrauthor | Swales, Karen | |
dc.contributor.icrauthor | Matthews, Thomas | |
dc.contributor.icrauthor | McHardy, Tatiana | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Eccles, Suzanne | |
dc.contributor.icrauthor | Collins, Ian | |