Targeting undruggable intrinsically disordered regions in childhood malignant neoplasms

We are dedicated to advancing the understanding of undruggable proteins and their role in cancer. Our research focuses on a specific category of proteins that lack stable drug-binding pockets, making them challenging to target effectively.

In particular, we investigate intrinsically disordered proteins (IDPs) and regions (IDRs), which are characterized by their lack of a fixed three-dimensional structure. These proteins play critical roles in forming protein-protein and protein-DNA interactions, mainly driven by electrostatic forces. The resulting fuzzy complexes exhibit dynamic behavior and structural heterogeneity throughout the protein.

Our lab aims to design covalent binders for these extended interaction interfaces, overcoming the obstacles of off-target effects and potency. We explore innovative strategies to tackle the inherent complexity of IDPs, leveraging their versatility in binding while maintaining selectivity and avoiding off-target toxicity.

Understanding the functional significance of IDPs is crucial, as they have been found to be central in signaling pathways, post-translational modifications, and the regulation of essential cellular processes. Moreover, IDPs are frequently associated with cancer, acting as either oncosuppressor or oncogenes. However, their precise functions and contributions to cancer development remain poorly characterized.

Through our research, we aim to shed light on the molecular mechanisms underlying cancer insurgence. By employing cutting-edge techniques such as the AlphaFold2 method, we can accurately predict protein structures and apply a rational approach to study cancer-associated IDPs. Our investigations involve the characterization of childhood malignant neoplasm proteins, focusing on recurrent targets and exploring allosteric communication mechanisms to potentially make undruggable targets druggable.

Additionally, we delve into the intricate interplay between globular and disordered domains within the selected protein systems. By examining their conformational heterogeneity, interactome, binding pockets, and ligands, we aim to decipher the complex regulatory networks involving IDPs.

Our research has significant implications for cancer therapy. Childhood malignant neoplasms, in particular, represent a challenging and understudied area. By uncovering the molecular intricacies of these poorly characterized cancers, we aim to provide physicians with additional tools to improve treatment outcomes.

At our lab, we adopt a multidisciplinary approach, combining state-of-the-art predictions from AlphaFold2 with in-house software specifically developed to analyze IDPs. This unique combination allows us to address the complex nature of IDPs and bridge the gap in structural biology research.