What are the advantages of covalent inhibitors?

Covalent inhibitors are chemicals that form a covalent bond with their target proteins, usually modifying them irreversibly and causing them to lose their function. This can have advantages and disadvantages.

The primary advantage of covalent inhibitors is their ability to form strong, permanent bonds with their target proteins, effectively blocking the target protein’s activity for a prolonged period. This results in enhanced potency of the drug and more sustained therapeutic effects, so the drug can be administered in lower doses with larger intervals between doses, potentially improving compliance, reducing the risk of side effects, and lowering the cost of treatments. 

Another advantage of covalent inhibitors is that they exhibit significant selectivity, engaging their intended targets in a precise manner. This characteristic enables them to target even challenging proteins, such as those that lack conventional binding pockets. One such example is KRAS, the most commonly mutated oncogene that was previously considered to be untreatable using drugs. KRAS can now be targeted successfully using sotorasib, a covalent inhibitor.