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Structure-Based Design of Novel, Urea-Containing FKBP12 Inhibitors

1996; American Chemical Society; Volume: 39; Issue: 9 Linguagem: Inglês

10.1021/jm950798a

1520-4804

Peter S. Dragovich, John E. Barker, J. V. FRENCH, Michael Imbacuan, Vincent J. Kalish, Charles R. Kissinger, Daniel R. Knighton, Cristina Lewis, Ellen W. Moomaw, Hans E. Parge, Laura A. Pelletier, Thomas J. Prins, Richard E. Showalter, John H. Tatlock, Kathleen D. Tucker, J. Ernest Villafranca,

Toxin Mechanisms and Immunotoxins

The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (Ki,app) approaching 0.10 microM. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.