FlexCAT

Traditionally, proteins have been categorized into two main structural classes: ordered and disordered. Large parts of the human proteome contain intrinsically disordered regions (IDRs), which are highly flexible and only sometimes adopt a distinct conformation upon interaction with a binding partner. IDRs are fundamental to intracellular signalling and protein interaction networks, particularly transcriptional regulation. Dysregulation of these processes is strongly associated with diseases including cancer and neurodegenerative disorders. However, targeting IDRs is challenging because of their dynamic nature and the lack of well-defined binding pockets. IDR targets have therefore been largely underrepresented in the pharmaceutical industry and the competencies for characterizing and targeting IDRs are lacking. The aim of the FlexCAT doctoral training network (DN) is to equip a cohort of doctoral candidates (DCs) with unique expertise and knowledge in characterizing and targeting IDRs. We aim to challenge and complement the limitations of classical small molecule approaches that were primarily developed to target druggable pockets within folded proteins. The DCs will carry out challenging research projects with the aim to assemble, expand, develop and apply novel approaches to understand and exploit disordered targets and IDRs. We will focus on utilizing β-catenin, a central therapeutic target and prime example of an IDR-related drug targeting challenge. Alongside the individual research projects, the DCs will expand their knowledge and transferrable skills through a structured training program, including secondments and contributions from the non-academic sector. The outcome of the FlexCAT DN will be increased understanding of the role of disordered targets and IDRs, their implications in disease and particularly cancer, while also developing practical strategies for exploring the therapeutic intervention of alternative IDR-related protein targets.