Structure-activity relationships for 2-anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones as inhibitors of the cellular checkpoint kinase Wee1.
A series of 2-anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones were synthesized and evaluated for their inhibitory properties against the non-receptor kinase c-Src and the G2/M checkpoint kinase Wee1. Overall, the compounds were 10-100-fold more potent inhibitors of c-Src than Wee1, and variation of substituents on the 6-phenyl ring did not markedly alter this preference. Solubilizing substituents off the 2-anilino ring in many cases increased Wee1 activity, thus lowering this preference to about 10-fold. 5-Alkyl substituted analogs were generally Wee1 selective, but at the expense of absolute potency.
Palmer
Brian D
BD
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. b.palmer@auckland.ac.nz
Smaill
Jeff B
JB
Rewcastle
Gordon W
GW
Dobrusin
Ellen M
EM
Kraker
Alan
A
Moore
Charles W
CW
Steinkampf
Randall W
RW
Denny
William A
WA
D000814:Aniline Compounds / Q000737:chemistry; D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009287:Naphthyridines / Q000737:chemistry; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D019061:src-Family Kinases
D000814:Aniline Compounds; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D009687:Nuclear Proteins; D011744:Pyrimidinones; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C499349:WEE1 protein, human; D019061:src-Family Kinases; C000631346:CSK protein, human; D000071877:Checkpoint Kinase 1; C023650:aniline