| Abstract: |
We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML. © 2009 Elsevier Ltd. All rights reserved. |
| Keywords: |
controlled study; unclassified drug; human cell; antineoplastic agents; pyridines; drug targeting; imatinib; stem cell factor receptor; vasculotropin receptor; enzyme inhibition; antineoplastic activity; cancer cell culture; drug potency; cell line, tumor; abl kinase; cml; inhibitor; pyridopyrimidines; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; 6 (2,6 dichlorophenyl) 8 methyl 2 (phenylamino)pyrido[2,3 d]pyrimidin 7 one; abelson kinase; dasatinib; platelet derived growth factor receptor; protein serine threonine kinase; protein tyrosine kinase; pyrimidinone derivative; recombinant enzyme; cell assay; chronic myeloid leukemia; drug design; drug selectivity; drug specificity; drug synthesis; structure activity relation; substitution reaction; oncogene proteins v-abl; pyridones; pyrimidines; pyrimidinones; structure-activity relationship
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