Broad implementation of a novel warhead for covalent protein modification

Covalent drugs incoroporate a reactive functional group that forms a covalent bond with a specific molecular target thereby inhibiting its function. Although historically small molecules with reactive groups have been avoided in medicinal chemistry due to potential off-target reactivity, optimised drug design sparked an improved perception of their selectivity and safety and led to a substantial rise in market approval in the past decade. Recently different kinases have been successfully targeted with covalent inhibitors and KRAS, which for long time has been thought undruggable, is now effectively targeted by mutant-selective covalent KRAS(G12C) inhibitors. Advantages of covalent drugs are additional affinity, sustained target engagement and increased potency. Several nucleophilic amino acids may be targeted by covalent interactors and there exist different chemical strategies (warheads) for covalent modulation of these residues. Recently, we have discovered a completely novel covalent warhead, for which we have demonstrated potent in vitro as well as in vivo activity against a specific target. Here we aim to investigate whether this warhead can be widely applied to modulate a broad variety of protein targets involved in disease.

Keywords:CRISPR/Cas9-mediated mutagenesis, warhead, structure-aided modeling, covalent drug, nucleophilic aromatic substitution, cancer

Disciplines:Medicinal chemistry