137(P-90) 両特異性プロテインホスファターゼVHR阻害剤の設計と合成(ポスター発表の部)

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VHR is a dual-specificity phosphatase which is known to dephosphorylate activated ERK, a member of MAP kinase family, and negatively control ERK-mediated cell proliferating signals. Development of specific inhibitor of VHR would be useful for analysis of the ERK signaling in various cells. A naturally occurring tetronic acid derivative, RK-682, was known to inhibit VHR. Here we report a mechanism of VHR inhibition by RK-682, rational design of novel inhibitor based on this mechanism, and its synthesis and evaluation. First we developed an efficient and versatile synthetic route to RK-682. Next, by the synthesis and evaluation of related derivatives 1-31, basic structure-activity relationship (SAR) of these compounds as VHR inhibitor was clarified. The SAR is summarized as follows: (i) free tetronic acid moiety is essential for the inhibition, (ii) replacement of 3-acyl group to alkyloxycarbonyl or alkylthiocarbonyl group does not affect the inhibition, (iii) long hydrophobic side chain at C3-position is required for full inhibition, and (iv) hydroxy group at C5-position does not positively interact with VHR. On the other hand, kinetic analysis on the inhibition of VHR by RK-682 was also carried out, suggesting two molecules of RK-682 were involved in the inhibition of VHR. Based on these informations and a reported crystal structure of VHR, we constructed a RK-682-VHR binding model using molecular mechanics and molecular dynamics calculations. As shown in Figure 4, tetronic acid group of the first RK-682 molecule interacts with the active site loop of VHR, and that of the second one interacts with the basic Arg_<158> pocket. The hydrophobic side chains at C3-position of two RK-682 interact with each other and also with the hydrophobic amino acid residues existing near active site of VHR. Finally, we designed a dimer-type molecule 32 based on the binding model of RK-682 (Figure 5). Synthesis of 32 in optically active form was accomplished as shown in Figure 6. As expected, this designed dimer molecule 32 inhibited VHR with the IC_<50> value of 1.8μM which is one order of magnitude lower than that of RK-682. In contrast, the synthetic intermediates 37 and 39 showed the similar IC_<50> values to that of RK-682 indicating the importance of the second tetronic acid group. These experimental results clearly support our binding model.
天然有機化合物討論会の論文
2000-10-01

137(P-90) 両特異性プロテインホスファターゼVHR阻害剤の設計と合成(ポスター発表の部)

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