BML-257, a Small Molecule that Protects against Drug-Induced Liver Injury in Zebrafish.

ABSTRACT

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug-induced liver injury (DILI) would be invaluable in such situations. We used a transgenic line in zebrafish with a hepatocyte-specific expression of bacterial nitroreductase to cause temporally controlled liver damage. A whole organism-based chemical screen using the transgenic line identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 was tested in two independent toxicological models of liver injury caused by acetaminophen and isoniazid and was found to be protective against damage. This suggests that BML-257 has the potential to protect against multiple kinds of DILI.