Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity in Rodent Livers

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in rodent livers. Male Wistar Han rats were dosed p.o. once daily for seven days with 10, 30, or 100 mg/kg of GS-5801 or water (vehicle control). 100 mg samples of liver tissue (left lateral lobe) were collected, snap frozen using liquid nitrogen, and stored at -80 °C for subsequent transcriptome analysis by RNAseq.