Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 3: Importance of the indole orientation.
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 10nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core of the inhibitors. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Lu
Qing
Q
Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
Chen
Zheng
Z
Perumattam
John
J
Wang
Dan-Xiong
DX
Liang
Weiling
W
Xu
Yong-Jin
YJ
Do
Steven
S
Bonaga
Llorente
L
Higaki
Jeffrey
J
Dong
Hanmin
H
Liclican
Albert
A
Sideris
Steve
S
Laney
Maureen
M
Dugar
Sundeep
S
Mavunkel
Babu
B
Levy
Daniel E
DE
D000255:Adenosine Triphosphate / Q000378:metabolism; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008301:Maleimides / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D000255:Adenosine Triphosphate; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2