Drug discovery for a new generation of covalent drugs

Abstract

INTRODUCTION: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochemical efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clinical trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. AREAS COVERED: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chemical/biochemical reactivity assays that aim to provide a systematic rank ordering of pharmacologic selectivity relative to off-target protein reactivity of covalent inhibitors. EXPERT OPINION: While tactics to examine selective covalent modification of the pharmacologic target are broadly applicable in drug discovery, it is unclear whether the output from such studies can prospectively predict idiosyncratic immune-mediated drug toxicity. Opinions regarding an acceptable threshold of protein reactivity/body burden for a toxic electrophile and a non-toxic electrophilic covalent drug have not been defined. Increasing confidence in proteomic and chemical/biochemical reactivity screens will require a retrospective side-by-side profiling of marketed covalent drugs and electrophiles known to cause deleterious toxic effects via non-selective covalent binding.