2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.
MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.
Argiriadi
Maria A
MA
Abbott Laboratories, 100 Research Drive, Worcester, MA 01605-5314, USA.
Ericsson
Anna M
AM
Harris
Christopher M
CM
Banach
David L
DL
Borhani
David W
DW
Calderwood
David J
DJ
Demers
Megan D
MD
Dimauro
Jennifer
J
Dixon
Richard W
RW
Hardman
Jennifer
J
Kwak
Silvia
S
Li
Biqin
B
Mankovich
John A
JA
Marcotte
Douglas
D
Mullen
Kelly D
KD
Ni
Baofu
B
Pietras
M
M
Sadhukhan
Ramkrishna
R
Sousa
Silvino
S
Tomlinson
Medha J
MJ
Wang
Lu
L
Xiang
Tao
T
Talanian
Robert V
RV
D000255:Adenosine Triphosphate / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
D000255:Adenosine Triphosphate; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D000099190:MAP-Kinase-Activated Kinase 2; C017205:2,4-diaminopyrimidine