Pyrimidine-based inhibitors of CaMKIIdelta.
Non-ATP competitive pyrimidine-based inhibitors of CaMKIIdelta were identified. Computational studies were enlisted to predict the probable mode of binding. The results of the computational studies led to the design of ATP competitive inhibitors with optimized hinge interactions. Inhibitors of this class possessed improved enzyme and cellular activity compared to early leads.
Mavunkel
Babu
B
Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
Xu
Yong-Jin
YJ
Goyal
Bindu
B
Lim
Don
D
Lu
Qing
Q
Chen
Zheng
Z
Wang
Dan-Xiong
DX
Higaki
Jeffrey
J
Chakraborty
Indrani
I
Liclican
Albert
A
Sideris
Steve
S
Laney
Maureen
M
Delling
Ulrike
U
Catalano
Rosanne
R
Higgins
Linda S
LS
Wang
Hui
H
Wang
Jing
J
Feng
Ying
Y
Dugar
Sundeep
S
Levy
Daniel E
DE
D000255:Adenosine Triphosphate / Q000378:metabolism; D001667:Binding, Competitive; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C030986:pyrimidine