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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

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

T Usui, S Kojima, S Kidokoro, K Ueda, H Osada, M Sodeoka

Chem Biol. 2001 Dec;8(12):1209-20.

PMID: 11755399

Abstract:

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.
Conclusion:
We have developed a novel inhibitor of VHR based on the results of kinetic analysis and docking simulation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP150627375	RK-682		150627-37-5	Price

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