Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2).
A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.
Lovering
Frank
F
Chemical Sciences, Wyeth Research, Cambridge, MA 02140, USA. flovering@wyeth.com
Kirincich
Steve
S
Wang
Weiheng
W
Combs
Kerry
K
Resnick
Lynn
L
Sabalski
Joan E
JE
Butera
John
J
Liu
Julie
J
Parris
Kevin
K
Telliez
J B
JB
D001665:Binding Sites; D045744:Cell Line, Tumor; D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009000:Monocytes / Q000166:cytology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021381:Protein Transport; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D003503:Cyclobutanes; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; C030042:squaric acid