Conformationally Locked Isostere of PhosphoSer−cis-Pro Inhibits Pin1 23-Fold Better than PhosphoSer−trans-Pro Isostere

• Published in: Journal of the American Chemical Society 2004-12, Vol.126 (47), p.15533-15542
• Main Authors: Wang, Xiaodong J, Xu, Bailing, Mullins, Ashley B, Neiler, Freda K, Etzkorn, Felicia A
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cell Line, Tumor; Conformational dynamics in molecular biology; Dipeptides - chemistry; Dipeptides - pharmacology; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Humans; Kinetics; Molecular biophysics; NIMA-Interacting Peptidylprolyl Isomerase; Ovarian Neoplasms - drug therapy; Peptidylprolyl Isomerase - antagonists & inhibitors; Phosphoserine - analogs & derivatives; Proline - analogs & derivatives; Protein Conformation; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja046396m

Stereoisomeric cis and trans substrate analogues for Pin1 were designed and synthesized. The central phosphoSer−Pro core of the Pin1 substrate was replaced by cis and trans amide isosteres in Ac−Phe−Phe−pSer−Ψ[(Z and E)CHC]−Pro−Arg−NH2, 1 and 2, peptidomimetics. They were synthesized on solid phase in 17% yield for the cis analogue 1, and 16% yield for the trans analogue 2. A second trans amide isostere with a C-terminal N-methylamide 3 was synthesized in 7% yield. The protease-coupled Pin1 assay showed that all three compounds inhibited the Pin1 peptidyl-prolyl isomerase (PPIase) enzymatic activity. The cis isostere 1 was 23 times more potent (K i = 1.74 ± 0.08 μM) than its trans counterpart 2 (K i = 40 ± 2 μM) in competitive inhibition of Pin1. These results suggest that the catalytic site of Pin1 binds cis substrates more tightly in aqueous solution. Antiproliferative activity toward the A2780 human ovarian cancer cell line by the cis and trans analogues correlates with Pin1 inhibition results.