Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase: implications for the molecular mechanism of the inhibition.
BACKGROUND
VHR is a dual-specificity phosphatase, which dephosphorylates activated ERK1/2 and weakens the ERK signaling cascade in mammalian cells. A selective inhibitor is expected to be useful for revealing the physiological function of VHR.


RESULTS
First, we investigated the molecular mechanism of VHR inhibition by a known natural product, RK-682. Kinetic analysis indicated that inhibition was competitive toward the substrate, and two molecules of RK-682 were required to inhibit one molecule of VHR. Based on the structure-activity relationships for VHR inhibition by RK-682 derivatives, we constructed a binding model using molecular dynamics calculation. Based on this model, we designed and synthesized a novel dimeric derivative. As expected, the dimeric derivative showed increased inhibition of VHR, supporting our proposed mechanism of VHR inhibition by RK-682.


CONCLUSIONS
We have developed a novel inhibitor of VHR based on the results of kinetic analysis and docking simulation.
Usui
T
T
Antibiotics Laboratory, RIKEN, Hirosawa, Saitama, Japan.
Kojima
S
S
Kidokoro
S
S
Ueda
K
K
Osada
H
H
Sodeoka
M
M
D019281:Dimerization; D015195:Drug Design; D054640:Dual Specificity Phosphatase 3; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000032:analysis* / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; C094097:RK 682; D010749:Phosphoprotein Phosphatases; D054640:Dual Specificity Phosphatase 3; D017027:Protein Tyrosine Phosphatases