Stereoisomeric cis and trans su
bstrate analogues for Pin1 were designed and synthesized. Thecentral phosphoSer-Pro core of the Pin1 su
bstrate was replaced
by cis and trans amide isosteres in Ac-Phe-Phe-pSer-
![](/images/gifchars/Psi.gif)
[(
Z and
E)CH=C]-Pro-Arg-NH
2,
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 inhi
bited the Pin1 peptidyl-prolyl isomerase (PPIase) enzymaticactivity. The cis isostere
1 was 23 times more potent (
Ki = 1.74 ± 0.08
![](/images/entities/mgr.gif)
M) than its trans counterpart
2 (
Ki= 40 ± 2
![](/images/entities/mgr.gif)
M) in competitive inhi
bition of Pin1. These results suggest that the catalytic site of Pin1
bindscis su
bstrates more tightly in aqueous solution. Antiproliferative activity toward the A2780 human ovariancancer cell line
by the cis and trans analogues correlates with Pin1 inhi
bition results.