Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
Ahn
Yu Mi
YM
Deciphera Pharmaceuticals LLC, 643 Massachusetts St, Lawrence, KS 66044, USA.
Clare
Michael
M
Ensinger
Carol L
CL
Hood
Molly M
MM
Lord
John W
JW
Lu
Wei-Ping
WP
Miller
David F
DF
Patt
William C
WC
Smith
Bryan D
BD
Vogeti
Lakshminarayana
L
Kaufman
Michael D
MD
Petillo
Peter A
PA
Wise
Scott C
SC
Abendroth
Jan
J
Chun
Lawrence
L
Clark
Robin
R
Feese
Michael
M
Kim
Hidong
H
Stewart
Lance
L
Flynn
Daniel L
DL
D000255:Adenosine Triphosphate / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C556098:DP 802; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000255:Adenosine Triphosphate; D048308:Mitogen-Activated Protein Kinase 14