Covalent inhibitors possess a functional group that reacts with a nucleophilic residue on a target protein to form a bond that inhibits the protein’s function. Historically, covalent inhibitors have been successfully developed into marketed drugs for a wide range of therapeutic targets, with examples like acetylsalicylic acid (aspirin), β-lactam antibiotics (penicillins), and in particular in the oncogenic area, with the likes of Ibrutinib (for the treatment of lymphoma and chronic lymphocytic leukaemia) and sotorasib (for the treatment of lung cancers with the KRASG12C mutation). Most drugs on the market pre-2000 were only later discovered to have a covalent mechanism of action, one of the most prominent examples being aspirin.

 While representing a significant portion of the available drugs on the market, the pharmaceutical industry has, until relatively recently, been reluctant to deliberately design covalent drugs. This was due to the perception that covalently modifying proteins could pose safety risks, such as autoimmune reactions like idiosyncratic liver toxicity. Designing and tuning the reactivity of the electrophilic warhead (the functional group that forms the covalent bond with the protein), to obtain a suitable selectivity and safety profile, can be challenging. It must balance chemical reactivity with selectivity while maintaining stability and efficacy. Additionally, specialised assays, resistance concerns, and species-specific differences add complexity. Advancements in structural biology, computational modelling, and screening techniques are helping to address these hurdles.