Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.
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.
Antczak
Christophe
C
Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10065, USA. antczakc@mskcc.org
Veach
Darren R
DR
Ramirez
Christina N
CN
Minchenko
Maria A
MA
Shum
David
D
Calder
Paul A
PA
Frattini
Mark G
MG
Clarkson
Bayard
B
Djaballah
Hakim
H
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
D000970:Antineoplastic Agents; D016374:Oncogene Proteins v-abl; C473352:PD 166326; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones