The Ascension of Targeted Covalent Inhibitors

摘要

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceuticalindustry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalentinhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting thecovalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized thetreatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical andfinancial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in thefield.Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlightsthe broad opportunity to deliver a new generation of breakthrough therapies.