ADAR1i-124 is a selective inhibitor of the ADAR1 A-to-I RNA editing activity with in vitro editing IC50 values of 10-30 uM, inhibits the catalytic activities of both ADAR1p150 and ADAR1p110.
ADAR1i-124 shows no substantial ADAR2 inhibitory activity at 300 μM.
ADAR1i-124 shows direct binding to ADAR1 with SPR Kd of 9.6 uM.
ADAR1i-124, like siAdar1, prompted the transition of certain dsRNAs from A-form to Z-form, reduced targeted mRNAs (Wdr76, Iws1, and Gnl3l), inhibited A-to-I editing at LTR- and SINE-dsRNA target sites.
ADAR1i-124 exhibits potent cytotoxicity against HeLa cells, with an IC50 of 0.17 uM, also induced DNA damage, M phase arrest, and apoptosis along with an increase in R-loop (RNA: DNA hybrid) formation.
ADAR1i-124 induces dose-dependent cytotoxicity in various mouse and human cancer cell lines (HGS2 ovarian cancer cell, IC50=1.2 uM), upregulates expression of IFN-stimulated genes (ISGs) such as Ifih1 (MDA5), Cxcl9, and Cxcl10 in Yumm1.7 melanoma and HGS2 ovarian cancer (OC) cells, indicating that ADAR1i-124 activates IFN signaling.
ADAR1i-124 induces IFN signaling through the MDA5 and ZBP1 pathways.
ADAR1i-124 inhibits only the A-to-I editing activity but not the dsRNA-binding functions of ADAR1.
DNA methylation inhibitor 5-Aza-CdR enhances the efficacy of ADAR1i-124 in dose-dependent eradication of certain cancer cell lines less responsive to ADAR1i-124 alone.