The discovery of carboline analogs as potent MAPKAP-K2 inhibitors.
The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.
Wu
Jiang-Ping
JP
Research and Development, Boehringer-Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, USA. jwu@rdg.boehringer-ingelheim.com
Wang
Ji
J
Abeywardane
Asitha
A
Andersen
Denise
D
Emmanuel
Michel
M
Gautschi
Elda
E
Goldberg
Daniel R
DR
Kashem
Mohammed A
MA
Lukas
Susan
S
Mao
Wang
W
Martin
Leslie
L
Morwick
Tina
T
Moss
Neil
N
Pargellis
Christopher
C
Patel
Usha R
UR
Patnaude
Lori
L
Peet
Gregory W
GW
Skow
Donna
D
Snow
Roger J
RJ
Ward
Yancey
Y
Werneburg
Brian
B
White
Andre
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002243:Carbolines; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2