1. Expanding the toolbox of E3 Ligases
Our group, in collaboration with the Barril’s Lab, is involved in the development of small-molecules that target novel E3 ubiquitin ligases in order to expand the toolbox of this protein family. E3 ubiquitin ligases are involved in the recruitment of a specific substrate protein marked to be degraded via the Ubiquitin Proteasome System, making them be very attractive candidates as drug targets. However, the development of small-molecules against E3 ligases has been rewarded with limited success, in part because modulating their activity and regulation requires targeting protein-protein interactions or allosteric sites. Small-molecules that target E3 ligases could not only be developed into chemical probes to elucidate the best pharmacological strategy to target a specific E3 ligase, but also serve as anchors to develop disease-specific PROTAC molecules.
2. Novel PROTACs for undruggable proteins
The majority of proteins are still today considered undruggable for conventional drug discovery approaches. An innovative approach that can address this situation is PROTACS (PROteolysis TArgeting Chimeric) moleculeS. PROTACS re-direct the intracellular degradation of any Protein of Interest (POI) by linking a ligand that binds to an E3 ligase on one side and that binds the POI on the other side. The action of PROTACS does not require a functional binding site and “theoretically” exerts its catalytic function through binding to any accessible protein surface. These features support the potential value of PROTACS as a revolutionizing therapeutic tool. Moreover, PROTACS emerges as a highly specific, robust and versatile approach to complement reverse genetic tools such as RNAi, CRISPR-CAS9 and other gene knockouts in the study of protein function, as it interferes at the post-translational level. The goal of the Galdeano’s Lab is to demonstrate that using PROTACS molecules, it is possible to expand the current druggable proteome.
3. Development of novel therapies for unmet medical needs
Our research mission is to discover novel small-molecules to provide tools for a better understanding of the biology processes, and to develop novel drugs to address unmet medical needs. To achieve this goal, we employ a multidisciplinary approach that combines biophysics, medicinal chemistry, molecular and cell biology and we work closely together with the computational chemistry lab lead by Prof. Xavier Barril. We are particularly strong in biophysical approaches for drug discovery, including DSF, SPR, ITC, ligand-based NMR and fluorescence techniques. Nowadays, biophysical methods are used extensively in hit finding (fragment-based screening), hit validation, in depth characterization of compound binding and lead optimization. In this line, we also have a deep knowledge of the lead optimization process to deliver molecules to the regulatory phase. We work on a wide breath of targets, internally and in collaborative projects.