Structure-Property Investigation of New "KetoFAPI" Inhibitors of Fibroblast Activation Protein (FAP): Discovery of Highly Potent, Selective Compounds with Prolonged Residence Times and Promising Radiotheranostic Potential

  • J Med Chem. 2025 Oct 23;68(20):21739-21765. doi: 10.1021/acs.jmedchem.5c02102.
Pawel Brzeminski  1 ,  Emile Verhulst  2 ,  Adrian Fabisiak  1 ,  Roberta Pacifico  1 ,  Daan Willocx  3 ,  Sarah Peeters  1 ,  Anke de Groot  2 ,  Sam Corthaut  2 ,  Kim Van Meel  2 ,  Sigrid Stroobants  3 ,  Koen Augustyns  1 ,  Maya Berg  4 ,  Anne-Marie Lambeir  2  4 ,  Frank Rösch  5 ,  Ingrid De Meester  2  4 ,  Filipe Elvas  3 ,  Pieter Van der Veken  1  4
Affiliations
  • 1. Laboratory of Medicinal Chemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Antwerp 2610, Belgium.
  • 2. Laboratory of Medical Biochemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Antwerp 2610, Belgium.
  • 3. Molecular Imaging and Radiology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Antwerp 2610, Belgium.
  • 4. Infla-Med Centre of Excellence, University of Antwerp, Antwerp 2610 , Belgium.
  • 5. Institut für Kernchemie, Johannes Gutenberg University of Mainz, Fritz-Strassman-Weg 2, Mainz D-55128, Germany.
PMID: 41086263 DOI: 10.1021/acs.jmedchem.5c02102
Abstract

Fibroblast activation protein α (FAP) is a serine protease that has emerged as an attractive, pan-cancer radiotheranostic target. The development of effective FAP-targeting radiotheranostics critically relies on the identification of FAP inhibitors that achieve prolonged tumor retention, thereby maximizing therapeutic efficacy and ensuring sustained tumor irradiation, regardless of radionuclide half-life considerations. Here, we present the design, synthesis, and biological evaluation of potent and selective FAP inhibitors bearing an electrophilic α-ketoamide warhead (ketoFAPIs). Through structure-activity relationship studies, we identified highly potent compounds with selectivity over prolyl oligopeptidase (PREP) by up to 3 orders of magnitude. Moreover, this manuscript shows for the first time that ketoFAPIs can exhibit significantly longer target residence times than first-generation FAPIs comprising an electrophilic carbonitrile warhead, which in turn translates into extended tumor retention in a mouse Cancer model. This work lays the groundwork for the use of ketoFAPIs as a versatile platform for the development of FAP-targeted radiopharmaceuticals.

Products