Targeted Covalent Inhibitors in Modern Drug Discovery: Mechanisms, Design Strategies, Clinical Applications and Future Perspectives

Targeted covalent inhibitors (TCIs) are an important group of drugs used in modern drug discovery. These drugs first bind to a specific protein and then form a strong covalent bond with it. This helps the drug stay attached to its target for a long time and can produce a longer-lasting effect. In the past, covalent drugs were associated with problems such as toxicity, immune reactions, and unwanted binding to other proteins. Advances in medicinal chemistry, structural biology, computer-based drug design, and chemo proteomics have helped scientists develop more selective and safer covalent drugs. Several covalent drugs, such as afatinib, osimertinib, ibrutinib, acalabrutinib, zanubrutinib, sotorasib, and adagrasib, have shown strong clinical success. Most of these drugs are used in cancer treatment. Their success has shown that covalent drugs can selectively target disease-related proteins and provide long-lasting therapeutic effects. This review explains the development and basic principles of targeted covalent inhibitors. It discusses how these drugs work, the different types of electrophilic warheads used to form covalent bonds, and the relationship between their chemical structure and activity. It also describes approved covalent drugs and their clinical uses. The review further discusses the main advantages and limitations of TCIs. It explains how cancer cells can develop resistance to these drugs and reduce their effectiveness. Special attention is given to important targets such as EGFR, BTK, and KRAS G12C, which have become major targets in cancer treatment. Finally, the review discusses the future of targeted covalent inhibitors. New applications are being studied in autoimmune diseases, infectious diseases, and neurological disorders. These developments may lead to safer, more selective, and more effective covalent drugs in the future.