sar-020106 and Colonic-Neoplasms

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.

Topics: Administration, Oral; Aminopyridines; Animals; Antineoplastic Agents; Checkpoint Kinase 1; Child; Colonic Neoplasms; DNA Damage; Drug Design; Humans; Mice; Mice, Nude; Mice, Transgenic; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Protein Kinase Inhibitors; Protein Kinases; Pyrimidines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays