Conformationally Locked Isostere of PhosphoSer-cis-Pro Inhibits Pin1 23-Fold Better than PhosphoSer-trans-Pro Isostere
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- 作者：Xiaodong J. Wang ; Bailing Xu ; Ashley B. Mullins ; Freda K. Neiler ; and Felicia A. Etzkorn
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：December 1, 2004
- 年：2004
- 卷：126
- 期：47
- 页码：15533 - 15542
- 全文大小：347K
- 年卷期：v.126,no.47(December 1, 2004)
- ISSN：1520-5126
文摘
Stereoisomeric cis and trans substrate analogues for Pin1 were designed and synthesized. Thecentral phosphoSer-Pro core of the Pin1 substrate was replaced by cis and trans amide isosteres in Ac-Phe-Phe-pSer-
[(Z and E)CH=C]-Pro-Arg-NH2, 1 and 2, peptidomimetics. They were synthesizedon solid phase in 17% yield for the cis analogue 1, and 16% yield for the trans analogue 2. A second transamide isostere with a C-terminal N-methylamide 3 was synthesized in 7% yield. The protease-coupledPin1 assay showed that all three compounds inhibited the Pin1 peptidyl-prolyl isomerase (PPIase) enzymaticactivity. The cis isostere 1 was 23 times more potent (Ki = 1.74 ± 0.08 
M) than its trans counterpart 2 (Ki= 40 ± 2 M) in competitive inhibition of Pin1. These results suggest that the catalytic site of Pin1 bindscis substrates more tightly in aqueous solution. Antiproliferative activity toward the A2780 human ovariancancer cell line by the cis and trans analogues correlates with Pin1 inhibition results.
[(Z and E)CH=C]-Pro-Arg-NH2, 1 and 2, peptidomimetics. They were synthesizedon solid phase in 17% yield for the cis analogue 1, and 16% yield for the trans analogue 2. A second transamide isostere with a C-terminal N-methylamide 3 was synthesized in 7% yield. The protease-coupledPin1 assay showed that all three compounds inhibited the Pin1 peptidyl-prolyl isomerase (PPIase) enzymaticactivity. The cis isostere 1 was 23 times more potent (Ki = 1.74 ± 0.08 M) than its trans counterpart 2 (Ki= 40 ± 2 M) in competitive inhibition of Pin1. These results suggest that the catalytic site of Pin1 bindscis substrates more tightly in aqueous solution. Antiproliferative activity toward the A2780 human ovariancancer cell line by the cis and trans analogues correlates with Pin1 inhibition results.