191471-32-6Relevant academic research and scientific papers
Structure-based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin)
Baba, Yoshiyasu,Hirukawa, Nozomu,Tanohira, Naoto,Sodeoka, Mikiko
, p. 9740 - 9749 (2007/10/03)
Protein serine/threonine phosphatases (PP1, PP2A and PP2B) play important roles in intracellular signal 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 on PP2B. Thus, it is of interest to find a direct and selective inhibitor of PP2B that does not involve the immunophilins as a biological tool for studies of PP2B and also as a candidate therapeutic agent. We selected the simple natural product cantharidin, a known PP2A-selective inhibitor, as a lead compound for this project. Primary SAR indicated that norcantharidin (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride) inhibits not only PP1 and PP2A but also PP2B, and a binding model of norcantharidin carboxylate to the PP2B catalytic site was computationally constructed. Based on this binding model, we designed and synthesized several cantharidin derivatives. Among these compounds, 1,5-dibenzoyloxymethyl-substituted norcantharidin was found to inhibit PP2B without inhibiting PP1 or PP2A. To our knowledge, this is the first highly selective catalytic site-directed inhibitor of PP2B.
Structure-based design of novel calcineurin (PP2B) inhibitors
Tatlock, John H.,Linton, M. Angelica,Hou, Xinjun J.,Kissinger, Charles R.,Pelletier, Laura A.,Showalter, Richard E.,Tempczyk, Anna,Villafranca, J. Ernest
, p. 1007 - 1012 (2007/10/03)
The design, synthesis, and evaluation of small molecule, in vitro, inhibitors of human calcineurin is described. These ligands were derived from the known nonspecific phosphatase inhibitor endothall, and were modified to enhance binding and selectivity toward calcineurin using protein crystal structure information.
