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Start Over Author "De Haven Brandon AK" Topic neuroblastoma
2 results on '"De Haven Brandon AK"'

1. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors.

Author

Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, and Collins I

Subjects
Administration, Oral, Aminopyridines chemical synthesis, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Checkpoint Kinase 1, Child, Colonic Neoplasms enzymology, DNA Damage drug effects, Drug Design, Humans, Mice, Mice, Nude, Mice, Transgenic, N-Myc Proto-Oncogene Protein, Neuroblastoma enzymology, Nuclear Proteins genetics, Oncogene Proteins genetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism, Pyrimidines chemical synthesis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Neuroblastoma drug therapy, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Pyrimidines pharmacology
Abstract

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.

Published
2012
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2. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs.

Author

Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, and Garrett MD

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Cycle Checkpoints drug effects, Checkpoint Kinase 1, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Mice, Transgenic, Protein Kinase Inhibitors administration & dosage, Aminopyridines administration & dosage, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Neuroblastoma drug therapy, Neuroblastoma metabolism, Protein Kinases genetics, Protein Kinases metabolism, Pyrimidines administration & dosage
Abstract

Purpose: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity., Experimental Design: Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay., Results: CCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma., Conclusion: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies., (©2012 AACR)

Published
2012
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