Structural modification of Fas C-terminal tripeptide and its effects on the inhibitory activity of Fas/FAP-1 binding.

We report the structural requirements of the C-terminal tripeptide derivative of Fas (Ac-Ser-Leu-Val-OH, 1) for the inhibitory activity of Fas/FAP-1 binding. The presence of a carboxyl group and a L-Val residue at the C-terminus is essential for the inhibitory activity, and the hydroxyl group of Ser plays an important role as the donor of a hydrogen bond. The introduction of hydrophobic groups to the N-terminal region of 1, especially the phenylaminocarbonyl group (41), showed a remarkable increase in potency. Further improvement was observed by the attachment of the Glu residue to the meta-position of the phenyl ring of 41 (51). The ester derivative of 41 (56) had the ability to induce apoptosis which was dependent on the concentration of anti-Fas antibody in the colon cancer cell line, DLD-1, which expresses both Fas and FAP-1 and is resistant to Fas-induced apoptosis. We are now investigating whether FAP-1 is a main target of 56 and whether the inhibition of Fas/FAP-1 binding by 56 retrieves the apoptotic signal.