I've been asked several times before why we don't use more "kill-it-dead-forever" (another way to look at covalent inhibitors like Ibrutinib) Covalent inhibito

I've been asked several times before why we don't use more "kill-it-dead-forever" (another way to look at covalent inhibitors like Ibrutinib) Covalent inhibitors are quite tricky to work with because every drug, no matter how specific has some off target effects. If your non-covalent drug accidentally binds to something it shouldn't, after a little while it'll go on its merry way (assuming the kinetics aren't awful). This means some side-effect regarding that protein it bound, but nothing permanent. On the other hand if a covalent inhibitor hits something it shouldn't, then that protein it hit is SOL, and gone until a new copy of it can be made. This could take a very long time in certain cases, causing much longer lasting effects. As a result, side-effects with covalent drugs can be both more severe and more variable. This is one reason that although they are popular in some areas of lab biochemistry, they haven't made as much of an impact in the broader clinic. In this particular case, the specificity of the drug, the importance of the target to the disease mechanism, and the patient population all combine to make it viable. However, it doesn't mean the next covalent inhibitor that comes along will work as well.