PROTAC-PDAC · Targeted Protein Degradation as a New Experimental and Therapeutic Approach for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease with few treatment options. Recently, the chemical space for targeted therapeutics was significantly increased by the development of compounds that induce protein degradation (PROTACs), but so far, they are unavailable for PDAC. The main motivation of PROTAC-PDAC is to develop novel targeted therapies for PDAC. The project is based on our accomplishments in three crucial areas. First, my group identified – as target candidates – a series of transcription factors that are absolutely required for PDAC growth in vivo. Second, we developed dozens of potent, specific PROTACs, thereby gaining deep insight into the underlying design principles and synthesis procedures. Third, we established genetic models in mice for simulating PROTAC function and discovering ideal target–E3 ligase pairs. In PROTAC-PDAC, we will develop compounds that degrade key oncogenic transcription factors and inhibit pancreatic tumor growth with minimal toxicity in healthy tissues. We will start by implementing the Auxin degron system in a murine PDAC model, to induce degradation of the target candidates and select four priority targets with the highest therapeutic index (Aim I). Then, we will assess their oncogenic functions by analyzing molecular, cellular and organismic consequences of acute depletion in mice (Aim II). In parallel, we will develop pharmaceutical PROTACs to induce target degradation and analyze their efficacy in PDAC models (Aim III). Finally, with the aim of developing less toxic PDAC therapy, we will identify pancreatic E3 ligases for the design of the first tissue-specific PROTACs that induce target degradation primarily in pancreatic tumor cells (Aim IV).While the main goal of PROTAC-PDAC is to develop new PROTAC-based therapeutic strategies, we will also establish groundbreaking methods and models leading to fundamental discoveries in PDAC biology.