Periodic Reporting for period 1 - TRPLigDrugConj (TRPV1-targeted ligand-drug conjugates to treat prostate cancer) Reporting period: 2017-03-01 to 2019-02-28 Summary of the context and overall objectives of the project Cancer remains a global health threat, in some cases, with limited therapies available. Prostate cancer is one of the most prevalent cancer types in male individuals and new, selective medications, ideally with new modes of action are urgently sought after. In this project we explore both a new mechanism of action and chemical entities to treat prostate cancer. The project tackles a major societal challenge and aims at validating a therapeutic strategy for future development. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The project is comprised of several tasks that build on each other towards the end goal, as described below:1) validation of the drug target in prostate cancer. A range of chemical and bioinformatics techniques were employed to assert the importance of the studied drug target. In particular we found that the target is not only relevant for personalized medicines, but can serve as a marker for diagnostic of prostate cancer;2) design and synthesis of small molecules that bind to the studied drug target. The task equally involved the biochemical profiling of all synthesized chemical entities.3) synthesis of chemical imaging probes to study the dynamics of the studied drug target. The task involved in vitro chemical reaction for optical imaging and tracking of the dynamics via microscopy.4) design and synthesis of conjugate systems targeting the protein under study. The task involved not only the synthesis of conjugate molecules, but also the study of their stability under simulated physiological conditions.5) In vitro profiling of the synthesized conjugate molecules, in a prostate cancer cell line. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The project exploits a new paradigm in molecular medicine, by conjugating a ligand molecule and cytotoxic agent. This way, a new entity is obtained that will selectively target diseased cells. Using this approach one can not only mask the cytotoxic effects of the therapy, but also ascertain an effective concentration of the therapeutics at the tumor site. Altogether, the strategy is expected to increase treatment efficiency in patients over expressing the drug target under study. Also, the strategy exploits a new mechanism of action, that has been proven selective for cancer and thereby reducing potential side effects exerted by the cytotoxic agent. Summary of strategy
