1. Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors
- Author
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Melanie Valenti, Michelle D. Garrett, Thomas P. Matthews, Ian Collins, John C. Reader, Paul D. Eve, T. McHardy, Alexis De Haven Brandon, Gary Box, Suzanne A. Eccles, Michael Lainchbury, G. Wynne Aherne, Angela Hayes, Kathy Boxall, Florence I. Raynaud, and Michael I. Walton
- Subjects
Drug ,DNA damage ,media_common.quotation_subject ,Cell ,Administration, Oral ,Aminopyridines ,Mice, Nude ,Antineoplastic Agents ,Mice, Transgenic ,Pharmacology ,Article ,Mice ,Neuroblastoma ,Pharmacokinetics ,In vivo ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Potency ,Animals ,Humans ,CHEK1 ,Child ,Protein Kinase Inhibitors ,media_common ,Oncogene Proteins ,N-Myc Proto-Oncogene Protein ,Chemistry ,Nuclear Proteins ,Xenograft Model Antitumor Assays ,Bioavailability ,medicine.anatomical_structure ,Pyrimidines ,Drug Design ,Checkpoint Kinase 1 ,Colonic Neoplasms ,Molecular Medicine ,Protein Kinases ,DNA Damage - 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