KDM5-C70 (GS-5801) is a cell-permeable derivative of KDM5-C49 (GS-080), potent, selective and cell permeable KDM5 inhibitor with IC50 of 0.3, 0.3 and 0.58 uM for KDM5A, B and C, respectively.
KDM5-C70 (GS-5801) significantly increases global levels of H3K4me3, while having little impact on H3K4me2/me1, or modifications regulated by other histone lysine demethylases, such as H3K27me3 (substrate for the KDM6 family) and H3K9me3/H3K36me3 (substrates for the KDM4 family).
KDM5-C70 (GS-5801) inhibits HBV RNA (EC50=0.16 uM), DNA (EC50=0.24 uM), and antigens (secreted HBsAg EC50=0.14 uM) in primary human hepatocytes.
GS-5801 exhibits antiviral activity across HBV genotypes.
GS-080 is a potent and selective inhibitor of KDM5 with IC50 of 0.36 nM against KDM5A and 0.38 nM against KDM5B, respectiveluy, displays 13-fold selectivity for KDM5A and KDM5B over members of the KDM4 family of enzymes, > 1,100- to > 278,000-fold over members of the other KDM enzyme families.
GS-5801 (10 uM) causes sustained HBV antigen suppression in primary human hepatocytes (PHH).
GS-5801 causes global increases in H3K4me3:H3 that precede antiviral activity, influences host and viral gene transcription.
GS-5801 is liver-targeted in nonclinical species and preferentially increases H3K4me3:H3 levels in the liver.
GS-5801 demonstrates antiviral activity in a PHH model of HBV infection that correlates with increases in global cellular H3K4me3:H3 ratio, but no antiviral activity is seen in the humanized mouse model of HBV infection.