A Translational Drug Screening Platform for Improving the Safety of First-Line Anti-Cancer Therapeutics

Abstract

Despite the potency of most first-line anti-cancer drugs, non-adherence to these drug regimens remains high and is attributable to the prevalence of “off-target” drug effects that result in serious, adverse events (SAEs) like hair loss, vomiting, and diarrhea. Some anti-cancer drugs are converted by homeostatic host metabolism to form drug-glucuronide conjugates; these sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, β-glucuronidase (bGUS) enzymes expressed by commensal gut bacteria can remove glucuronic acid moieties, producing reactivated drugs and triggering dose-limiting side effects. Small-molecule bGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of a novel chemical series of bGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for bGUS and applied them to largescale vHTS against ~400,000 compounds within the chemical libraries of the National Institutes of Health. From the vHTS results, we cherrypicked 291 compounds via a multifactor prioritization procedure, providing 68 diverse chemotypes that exhibited inhibitory activity in a follow-up bGUS biochemical assay in vitro. Our findings give a hit rate of 24% and could therefore inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with standard-of-care anti-cancer drugs.