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.
Sawa
E
E
Pharmaceutical Research Laboratory, Kirin Brewery Company, Ltd., 3 Miyahara-cho, Takasaki, Gumma 370-1295, Japan.
Takahashi
M
M
Kamishohara
M
M
Tazunoki
T
T
Kimura
K
K
Arai
M
M
Miyazaki
T
T
Kataoka
S
S
Nishitoba
T
T
D000906:Antibodies / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D009842:Oligopeptides; D019014:fas Receptor; C121209:phenylaminocarbonyl-seryl-leucyl-valine ethyl ester; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases