Colorectal cancer (CRC) shows about 450,000 new diagnosis/year in Europe and represent the most common cause of death in EU. Despiteactive prevention programs have been instituted in many European countries, including different Italian Regions, that efficiently contribute to thedecrease of the cases, the strong social impact is still high and resistance to most frequently used drugs require more work. High expectationsexist for advances from research on innovative drugs and cures are needed both in the Italian Health care system level and in the Horizon Europeresearch programmes. Motivated by this high medical need, we have focused on biological targets belonging to the Hippo pathway (HippoP),strongly involved in several processes of cancer promotion, progression and drug resistance. The transcriptional regulators YAP (Yes-associatedprotein) and TAZ (transcriptional co-activator) interact with TEAD and represent the major downstream effectors in this pathway. Deregulation ofthe HippoP offers a new opportunity for CRC cancer treatment.
Drug discovery programs directed to the HippoP targets are of high relevance for pharma, but the work published does not account for asufficiently extended efforts in the number and molecular diversity of the leads and drug candidates identified to ensure the development of aclinical candidate. In this context, we have proposed a multidisciplinary discovery plan to develop innovative leads showing cellular efficacy againstCRC cancer cells and clinical isolates provided by external hospital. Stemming from previously identified chemical probes, the aims of the presentproject are: 1. to develop new TEAD surface binding inhibitors at the interface of YAP:TEAD complex by targeting the exposed cys337 and itssurrounding area, thus preventing the complex formation, DNA binding and gene expression; 2. to characterize the selectivity of the inhibitorbinding to TEAD1-4; 3. To characterize the binding site on TEAD surface through a photoaffinity ligand assay through proteomic approach andfinally, 4. to evaluate the biological activity of the compounds on continuous colorectal cancer cells and apply a proteomic approach to characterizethe inhibition pathway in cells. As a preparatory work to de-risk our project and ensure its feasibility, we have developed successful preliminarywork on primary hits derivatization, FRET assay engineering and optical tweezers application. This action will allow us to achieve aims 1-3 within24 months.
The project novelty lies in its multidisciplinary approach, in which different expertise, namely, drug design, synthesis, biophysics, molecular andcancer biology, proteomics will ensure a sustainable approach for the synthesis of the final product. The project will recruit 3 young researchersand involve a PhD student. Innovation will be ensured by the high quality of the researchers and the frontier technologies employed.