Reactive Metabolite Screen for Reducing Candidate Attrition in Drug Discovery

Toxicity of drug candidates accounts for a significant portion of attrition during exploratory development. One common mode of toxicity is the formation of electrophilic reactive metabolites, which manifest their toxicity by covalent binding to nucleophilic groups present in vital cellular proteins and nucleic acids (1–2). Although not all toxicological manifestations are attributable to reactive metabolites, a vast body of literature suggests that inadequate detoxification of chemically reactive metabolites formed as a result of drug bioactivation is a pathogenic mechanism for tissue necrosis (3–4), carcinogenicity (5), teratogenicity (6) and immune-mediated toxicity (7).