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.
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Date
2016-01-19ICR Author
Author
Walton, MI
Eve, PD
Hayes, A
Henley, AT
Valenti, MR
De Haven Brandon, AK
Box, G
Boxall, KJ
Tall, M
Swales, K
Matthews, TP
McHardy, T
Lainchbury, M
Osborne, J
Hunter, JE
Perkins, ND
Aherne, GW
Reader, JC
Raynaud, FI
Eccles, SA
Collins, I
Garrett, MD
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
HT29 Cells
Animals
Mice, Inbred BALB C
Mice, Transgenic
Humans
Mice
Mice, Nude
Lymphoma, B-Cell
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
DNA Damage
4-Aminopyridine
Camptothecin
Pyrazines
Cyclin-Dependent Kinases
CDC2 Protein Kinase
Proto-Oncogene Proteins c-myc
Deoxycytidine
Antineoplastic Combined Chemotherapy Protocols
Xenograft Model Antitumor Assays
Apoptosis
Drug Synergism
Proto-Oncogene Proteins p21(ras)
Cell Cycle Checkpoints
Checkpoint Kinase 2
Checkpoint Kinase 1
Irinotecan
Research team
Cancer Pharmacology & Stress Response (CPSR)
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 2
Tumour Biology & Metastasis
Clinical PD Biomarker Group
Language
eng
Date accepted
2015-07-11
License start date
2016-01
Citation
Oncotarget, 2016, 7 (3), pp. 2329 - 2342
Publisher
IMPACT JOURNALS LLC