Covalent inhibition of protein-protein interaction (1): Development of covalent inhibitor based on N-acyl-N-alkyl sulfonamide (NASA) warhead

摘要

Protein-protein interactions (PPIs) play an important role in many cell signalling networks. Thus, control and modulation of PPIs would enable investigation of key biological events and lead to novel therapeutics. In general, the development of highly potent inhibitors for PPIs is quite difficult in comparison to other drug classes (receptors and enzymes etc.) because PPI interfaces do not usually contain a well-defined, deep binding pocket. To circumvent this limitation, targeted covalent inhibition of PPIs is recently considered to be promising strategy. However, PPI interfaces do not always contain a free cysteine residue which is widely targeted with conventional warheads, such as Michael acceptor or α-halocarbonyl group. Therefore, chemical modification of other nucleophilic residues other than Cys is highly desirable to extend protein scope for covalent PPIs inhibition.