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Your search keyword '"De Haven Brandon, Alexis K."' showing total 2 results
Start Over Author "De Haven Brandon, Alexis K." Journal oncotarget
2 results on '"De Haven Brandon, Alexis K."'

1. 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

Author

Walton, Mike I., Eve, Paul D., Hayes, Angela, Henley, Alan T., Valenti, Melanie R., De Haven Brandon, Alexis K., Box, Gary, Boxall, Kathy J., Tall, Matthew, Swales, Karen, Matthews, Thomas P., McHardy, Tatiana, Lainchbury, Michael, Osborne, James, Hunter, Jill E., Perkins, Neil D., Aherne, G. Wynne, Reader, John C., Raynaud, Florence I., Eccles, Suzanne A., Collins, Ian, and Garrett, Michelle D.

Subjects
Lung Neoplasms, Lymphoma, B-Cell, CHK1, Mice, Nude, Apoptosis, Mice, Transgenic, Irinotecan, environment and public health, CCT245737, Deoxycytidine, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Mice, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, CDC2 Protein Kinase, Animals, Humans, antitumor activity, 4-Aminopyridine, Mice, Inbred BALB C, biomarker assay, Drug Synergism, Cell Cycle Checkpoints, Xenograft Model Antitumor Assays, Gemcitabine, Cyclin-Dependent Kinases, enzymes and coenzymes (carbohydrates), Checkpoint Kinase 2, Pyrazines, Checkpoint Kinase 1, Camptothecin, biological phenomena, cell phenomena, and immunity, pharmacology, HT29 Cells, Research Paper, DNA Damage
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 exhibited1,000-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.

Published
2015

2. 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.

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, and Garrett MD

Subjects
4-Aminopyridine pharmacokinetics, 4-Aminopyridine pharmacology, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, CDC2 Protein Kinase, Camptothecin analogs & derivatives, Camptothecin pharmacology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Checkpoint Kinase 1 metabolism, Checkpoint Kinase 2 antagonists & inhibitors, Cyclin-Dependent Kinases antagonists & inhibitors, DNA Damage drug effects, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Drug Synergism, HT29 Cells, Humans, Irinotecan, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Pyrazines pharmacokinetics, Gemcitabine, 4-Aminopyridine analogs & derivatives, Carcinoma, Non-Small-Cell Lung drug therapy, Checkpoint Kinase 1 drug effects, Lung Neoplasms drug therapy, Lymphoma, B-Cell drug therapy, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins p21(ras) genetics, Pyrazines pharmacology, Xenograft Model Antitumor Assays
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.

Published
2016
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