Journal
FRONTIERS IN CHEMISTRY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2021.640566
Keywords
fibroblast activation protein; activity-based probe; fluorophore; biomarker; histochemistry
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Funding
- Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO) [1S64220N]
- Agentschap Innoveren en Ondernemen [VLAIO HCB 2019.2446]
- Kom op tegen Kanker, the Flemish cancer society [KotK_UA_l/2018/11471/1]
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Fibroblast activation protein (FAP) is a proline-selective protease highly expressed in the tumor microenvironment, and selective activity-based probes have been developed to detect FAP with subnanomolar affinity and selectivity. These probes are suitable for biological studies and have been tested for in situ FAP activity staining in patient-derived cryosections of urothelial tumors.
Fibroblast activation protein (FAP) is a proline-selective protease that belongs to the S9 family of serine proteases. It is typically highly expressed in the tumor microenvironment (TME) and especially in cancer-associated fibroblasts, the main cell components of the tumor stroma. The exact role of its enzymatic activity in the TME remains largely unknown. Hence, tools that enable selective, activity-based visualization of FAP within the TME can help to unravel FAP's function. We describe the synthesis, biochemical characterization, and application of three different activity-based probes (biotin-, Cy3-, and Cy5-labeled) based on the FAP-inhibitor UAMC1110, an in-house developed molecule considered to be the most potent and selective FAP inhibitor available. We demonstrate that the three probes have subnanomolar FAP affinity and pronounced selectivity with respect to the related S9 family members. Furthermore, we report that the fluorescent Cy3- and Cy5-labeled probes are capable of selectively detecting FAP in a cellular context, making these chemical probes highly suitable for further biological studies. Moreover, proof of concept is provided for in situ FAP activity staining in patient-derived cryosections of urothelial tumors.
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