Druglike FAPIs with maximal target residence time: from chemical discovery to preclinical evaluation in oncology and fibrosis theranostics

Fibroblast activation protein (FAP) is a protease biomarker that is selectively expressed on activated fibroblasts. Strongly FAP-positive fibroblasts are present in> 90% of all tumor types, in fibrotic disease lesions, and in other pathologies that involve tissue remodeling. Researchers at UAntwerpen earlier discovered UAMC1110: to date the most potent and selective FAP­-inhibitor described. UAMC1110 is now used widely as the FAP-targeting vector of the so-called FAPls: radiolabeled derivatives of UAMC1110. These FAPls can be used as diagnostics or as therapeutics ('theranostics'), depending on the radiolabel. Many UAMC1110-derived FAPls are currently in clinical development in oncology, 2 of which were co-developed preclinically by UAntwerp (collaboration with the Rosch group from Mainz).
While these FAPls have shown impressive clinical results in oncodiagnosis, radiotherapy applications are somewhat lagging. This is because the original FAPls typically have short FAP­ residence times, leading to short tissue retention and fast wash-out of radioactivity. To date, mainly optimization strategies that significantly discount on 'druglikeness' have been explored.
Examples include the use of 'multi-valency' and the addition of lipophilic, albumin-binding moieties. Remarkably, only a very limited number of papers have focused on optimizing the UAMC1110 pharmacophore. Some of these again have led to very large molecules. Druglikeness is not a critical parameter for most oncology applications, because of the leaky tumor vasculature and loose tissue.
In very dense tissue, such as in fibrosis, druglikeness can however be expected to become a key parameter.
The host recently discovered several series of druglike, pharmacophore-optimized FAPls, for which 3 patent applications were submitted in 2022 and 2023. We wish to investigate these molecules further and exploit their improved FAP-residence and druglikeness in oncology and fibrosis theranostics settings.