Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP)

  • ACS Med Chem Lett. 2019 Jul 9;10(8):1173-1179. doi: 10.1021/acsmedchemlett.9b00191.
An De Decker  1 ,  Gwendolyn Vliegen  2 ,  Dries Van Rompaey  1 ,  Anke Peeraer  1 ,  An Bracke  2 ,  Line Verckist  3 ,  Koen Jansen  1 ,  Ruth Geiss-Friedlander  4 ,  Koen Augustyns  1 ,  Hans De Winter  1 ,  Ingrid De Meester  2 ,  Anne-Marie Lambeir  2 ,  Pieter Van der Veken  1
Affiliations
  • 1. Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerp), Belgium.
  • 2. Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerp), Belgium.
  • 3. Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerp), Belgium.
  • 4. Institut für Molekularbiologie, Universitätsmedizin Göttingen, Humboldtallee 23, D-37073 Göttingen, Germany.
PMID: 31413802 DOI: 10.1021/acsmedchemlett.9b00191
Abstract

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.

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