Structure-Based Design of a Highly Selective Catalytic Site-Directed Inhibitor of Ser/Thr Protein Phosphatase 2B (Calcineurin)

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• 作者：Yoshiyasu Baba ; Nozomu Hirukawa ; Naoto Tanohira ; and Mikiko Sodeoka
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：August 13, 2003
• 年：2003
• 卷：125
• 期：32
• 页码：9740 - 9749
• 全文大小：617K
• 年卷期：v.125,no.32(August 13, 2003)
• ISSN：1520-5126

文摘

Protein serine/threonine phosphatases (PP1, PP2A and PP2B) play important roles in intracellularsignal transductions. The immunosuppressant drugs FK506 and cyclosporin A (CsA) bind to immunophilins,and these complexes selectively inhibit PP2B (calcineurin), leading to the suppression of T-cell proliferation.Both FK506 and CsA must, however, form complexes with immunophilins to exert their inhibitory action onPP2B. Thus, it is of interest to find a direct and selective inhibitor of PP2B that does not involve theimmunophilins as a biological tool for studies of PP2B and also as a candidate therapeutic agent. Weselected the simple natural product cantharidin, a known PP2A-selective inhibitor, as a lead compound forthis project. Primary SAR indicated that norcantharidin (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylicanhydride) inhibits not only PP1 and PP2A but also PP2B, and a binding model of norcantharidin carboxylateto the PP2B catalytic site was computationally constructed. Based on this binding model, we designed andsynthesized several cantharidin derivatives. Among these compounds, 1,5-dibenzoyloxymethyl-substitutednorcantharidin was found to inhibit PP2B without inhibiting PP1 or PP2A. To our knowledge, this is the firsthighly selective catalytic site-directed inhibitor of PP2B.