Abstract
Fibroblast activation protein (FAP) is a serine protease that is abundantly expressed on cancer-associated-fibroblasts (CAFs) in the micro-environment of nearly all tumor types. This makes FAP an ideal biomarker to selectively bring diagnostics and therapeutics to tumors. Currently, derivatives of UAMC1110, a very potent and selective FAP inhibitor developed by the host, are in clinical development as cancer diagnostics and therapeutics. These compounds often have relatively short tumor residence times, reducing their potential as therapeutics. In response, this proposal will optimize novel UAMC1110 analogues with significantly increased residence times. These new compounds ('ketoFAPIs') will be further transformed into 2 classes of innovative oncotherapeutics: [ketoFAPI-drug conjugates] and bispecific [ketoFAPI-HER2] Antibody-Drug Conjugates. The therapeutic potential of these compound types will subsequently be characterized in vitro and in tumor organoids. The most promising representative of both compound sets, will be selected for in vivo investigation in a murine model of breast cancer.
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