期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 6, 页码 2494-2501出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901778v
关键词
-
资金
- National Institutes of Health [GM062820, DK078965, HL093269]
- Pardee Foundation
Peptidylprolyl isomerase Pin1 regulates the (Unction and/or stability of phosphoproteins by altering the conformation of specific pSer/pThr-Pro peptide bonds. In this work, a cyclic peptide library was synthesized and screened against the catalytic domain of human Pin1. The selected inhibitors contained a consensus motif of D-pThr-Pip-Nal (where Pip is L-piperidine-2-carboxylic acid and Nal is L-2-naphthylalanine). Representative compounds were tested for binding to Pin I by isothermal titration calorimetry and inhibition of Pin1 activity, and the most potent inhibitors had K-D (and K-t) values in the low nanomolar range. Treatment of breast cancer cells with the inhibitors, which were rendered membrane permeable by attachment of an octaarginine sequence, inhibited cell proliferation and increased the protein levels of two previously established Pin1 substrates, PM L and SMRT. Finally, a second generation of cell permeable Pin1 inhibitors was designed by replacing the noncritical residues within the cyclic peptide ring with arginine residues and shown to have antiproliferative activity against the cancer cells.
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