Open AccessNovel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP)
Author(s) -
An De Decker,
Gwendolyn Vliegen,
Dries Van Rompaey,
Anke Peeraer,
An Bracke,
Line Verckist,
Koen Jansen,
Ruth GeissFriedlander,
Koen Augustyns,
Hans De Winter,
Ingrid De Meester,
AnneMarie Lambeir,
Pieter Van der Veken
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00191
Subject(s) - fibroblast activation protein, alpha , oligopeptidase , proteases , serine protease , peptide , small molecule , cancer research , biomarker , computational biology , chemistry , protease , medicine , biochemistry , bioinformatics , enzyme , biology , cancer
Fibroblast activation protein (FAP) is a proline-selective serine protease. It is hardly expressed in healthy adult tissue but upregulated in tissue remodeling sites associated with several diseases including epithelial cancer types, atherosclerosis, arthritis and fibrosis. Ongoing research aims at clinical implementation of FAP as a biomarker for these diseases. Several immunochemical methods that quantify FAP expression have been reported. An alternative/complementary approach focuses on quantification of FAP's enzymatic activity. Developing an activity-based assay for FAP has nonetheless proven challenging because of selectivity issues with respect to prolyl oligopeptidase (PREP). Here, we present substrate-type FAP probes that are structurally derived from a FAP-inhibitor (UAMC1110) that we published earlier. Both cleavage efficiency and FAP-selectivity of the best compounds in the series equal or surpass the most advanced peptide-based FAP substrates reported to date. Finally, proof-of-concept is provided that 4-aminonaphthol containing probes can spatially localize FAP activity in biological samples.