Cysteine-targeting covalent inhibition: recent trends and emerging strategies

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In the field of drug discovery, targeted covalent inhibitors (TCIs) have become popular due to their ability to form irreversible or reversible covalent bonds with target proteins, most frequently with cysteine. Covalent bonds offer prolonged target engagement, improved potency, and, in some cases, the ability to target proteins previously considered undruggable. TCIs can help in target validation and in obtaining information about protein function and binding sites. However, the development of TCIs is still very complex: it requires fine-tuning the warhead’s reactivity to avoid off-target effects and ensure the compound’s stability. This review addresses design and chemistry principles of cysteine-targeting covalent inhibitors, with a focus on the diversity of electrophilic warheads currently used or under research. Established motifs are discussed alongside newfound warheads. Recent advances in reversible covalent inhibition, metabolically labile warheads, and fragment-based electrophile screening are also addressed as strategies to improve TCIs specificity and safety. Despite the recent and substantial progress in the field, selectivity and safety remain major limitations for a broad application of TCIs. Therefore, continued innovation in warhead design is critical to develop new TCIs.