Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Abstract

Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?

“…The incorporation of drugs that bind covalently and reversibly to proteins would lead to lower toxicity by forming reversible adducts and thus reduce the risk of idiosyncratic toxicities caused by permanent modification of proteins, leading to higher levels of potential haptens [ 48 ].…”