Efficient degradation typically requires high affinity binding to the target as well as optimized linker geometry, to optimize the ternary complex formation. However, many targets such as transcription factors , protein-protein interfaces , or challenging enzyme classes such as GTPases , are recalcitrant to ligand discovery. This limits the applicability of PROTACs against such targets. A possible solution to this problem is to introduce an electrophile that will allow covalent binding to the target. However, irreversible binding may reduce potency by negating the catalytic nature of the PROTAC activity. While several covalent PROTACs have been developed and degrade their target successfully , there are examples in which the introduction of irreversible binding reduces the potency of PROTACs .