• Covalent protein kinase inhibitors and chemical probes
• Novel "warheads" for targeted covalent inhibitors
• Inhibitors of HECT-type E3 ubiquitin ligases
• Antibacterial protein-drug conjugates

Covalent protein kinase inhibitors and chemical probes

Covalent modifiers have a long history in drug discovery and many prominent blockbuster drugs (e.g. aspirin, omeprazole and β-lactam antibiotics) rely on their capability of forming a covalent bond with their protein target(s). However, the mechanism of action of such compounds was often discovered by serendipity. Despite the prevalence of covalent drugs, medicinal chemists were traditionally taught to consider reactive groups as liabilities that must be avoided due their anticipated promiscuity and potential immune-mediated toxicity. With the rise of specific "targeted covalent inhibitors" (TCIs) during the two past decades, we saw a paradigm shift and covalent approaches re-gained popularity in the medicinal chemistry community. Typical TCIs address a non-catalytic and poorly conserved amino acid residue with sufficient intrinsic nucleophilicity (usually a cysteine) by means of a weakly reactive electrophile (most frequently an α,β-unsaturated amide). Key advantages of properly designed TCIs include increased (apparent) potency, specificity and low competitivity, but also long-lasting pharmacodynamic effects that are mainly driven by the target's re-synthesis rate instead of the ligand's pharmacokinetic properties. This approach was very successful in the protein kinase field, where it has put forth over half a dozen of approved drugs in the last years. Moreover, covalent targeting turned out to be an extremely powerful strategy to generate specific chemical probes.

Protein kinases have become a major target class in drug discovery with over 50 small molecule protein kinase inhibitors (PKIs) being currently approved. Despite the success of PKIs, most drug discovery efforts were directed towards only few well-known targets while a significant part of the "kinome" (i.e. the over 500 human protein kinases) remains poorly characterized and lacks specific ligands. The human kinome features over 200 protein kinases with a non-catalytic cysteine located inside or close to the active site and many of these cysteines are poorly conserved. Additional ligandable cysteines can be found in allosteric pockets. A major part of our research aims at exploiting the kinases "cysteinome" for generating highly specific chemical probes to enable functional characterization (in vitro and in vivo) of kinases belonging to the "untargeted kinome". For relevant targets, further optimization and pre-clinical characterization is envisaged. In addition, our group pursues translational research projects aimed at the design and optimization of specific covalent inhibitors for protein kinases known to be involved in diseases, especially cancer.

Novel "warheads" for targeted covalent inhibitors

We have seen a rapid development in the TCI field during the last years. Nevertheless, the chemistry employed at the electrophilic "warhead" portion of such molecules remains severely limited, with α,β-unsaturated amides being almost exclusively used for cysteine targeting. Despite the wealth of electrophilic functional groups known from chemical research, systematic evaluations of alternative warheads for TCIs remain rare. We aim at filling this gap by investigation of non-conventional warhead chemistries for addressing protein kinases – but also other target classes. By using a variety of different chemical concepts, we further want to explore the ligandability of other non-catalytic amino acids like lysine, tyrosine or histidine, which feature a lower intrinsic reactivity compared to cysteine.

More details coming soon!