title: Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.
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.
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10065, USA. antczakc@mskcc.org
authors.forename: Christophe
authors.initials: C
authors.lastname: Antczak
authors.forename: Darren R
authors.initials: DR
authors.lastname: Veach
authors.forename: Christina N
authors.initials: CN
authors.lastname: Ramirez
authors.forename: Maria A
authors.initials: MA
authors.lastname: Minchenko
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.forename: Paul A
authors.initials: PA
authors.lastname: Calder
authors.forename: Mark G
authors.initials: MG
authors.lastname: Frattini
authors.forename: Bayard
authors.initials: B
authors.lastname: Clarkson
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016374:Oncogene Proteins v-abl; C473352:PD 166326; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones