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Your search keyword '"De Haven Brandon AK"' showing total 2 results
Start Over Author "De Haven Brandon AK" Topic 4-aminopyridine
2 results on '"De Haven Brandon AK"'

1. 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).

Author

Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, Brown N, Walton MI, Eve PD, Boxall KJ, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Jamin Y, Robinson SP, Westwood IM, van Montfort RL, Leonard PM, Lamers MB, Reader JC, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, and Collins I

Subjects
4-Aminopyridine chemical synthesis, 4-Aminopyridine chemistry, 4-Aminopyridine pharmacology, Checkpoint Kinase 1 metabolism, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazines chemical synthesis, Pyrazines chemistry, Structure-Activity Relationship, 4-Aminopyridine analogs & derivatives, Checkpoint Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazines pharmacology
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.

Published
2016
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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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