Covalent Bifunctional Molecules (CBMs): Achievements and Challenges

The burgeoning field of CBMs represents a significant stride in the evolution of targeted therapeutics. This class of compounds, characterized by their ability to form stable covalent bonds with specific proteins of interest (POIs) or biological effectors, has emerged as a promising avenue for addressing complex pathological conditions such as drug‐resistant diseases, undruggable targets, and chronic disorders requiring sustained target modulation. The integration of covalent chemistry in molecular design allows for the creation of highly specific and potent agents capable of modulating protein function with unprecedented precision. Herein, we meticulously classify CBMs according to the object of covalent bond formation and provide a discussion of the progress of CBMs since 2001, covering the design principles, molecular composition, covalent properties, and their reaction efficiencies, which not only reveals the potential of CBMs in drug discovery, but also emphasizes the importance of achieving innovations and breakthroughs in this field.