10 years into the resurgence of covalent drugs

In the first decade of targeted covalent inhibition, scientists have successfully reversed the previous trend that had impeded the use of covalent inhibition in drug development. Successes in the clinic, mainly in the field of kinase inhibitors, are existing proof that safe covalent inhibitors can be designed and employed to develop effective treatments. The case of KRAS(G12C) covalent inhibitors entering clinical trials in 2019 has been among the hottest topics discussed in drug discovery, raising expectations for the future of the field. In this perspective, an overview of the milestones hit with targeted covalent inhibitors, as well as the promise and the needs of current research, are presented. While recent results have confirmed the potential that was foreseen, many questions remain unexplored in this branch of precision medicine. Lay abstract If it is forever, it needs to be safe. Approved drugs on the market act with a multitude of different mechanisms, including both reversible and irreversible (permanent) inhibition of a target protein that is known to malfunction in a given disease. However, scientists are aware that increased side effects can potentially arise from irreversible drugs. Current research has focused on improving the safety of these drugs with the aim of developing more effective treatments. This perspective offers an overview of the current status of so-called 'targeted covalent inhibition' drug discovery.

Automated summary

In the first decade of targeted covalent inhibition, scientists have made significant progress in reversing the previous trend that hindered the use of covalent inhibition in drug development, especially in the field of kinase inhibitors. The successful entry of KRAS(G12C) covalent inhibitors into clinical trials in 2019 has sparked great interest in the future potential of this area of drug discovery. Despite the achievements, there are still many unanswered questions and areas for improvement in terms of safety and effectiveness.