The RNA editing
enzyme ADAR, is an attractive therapeutic target for multiple
cancers. Through its deaminase activity, ADAR edits
adenosine to
inosine in dsRNAs. Loss of ADAR in some
cancer cell lines causes activation of the
type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many
cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression:
8-azaadenosine and
8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both
8-azaadenosine and
8-chloroadenosine show similar toxicity to ADAR-dependent and independent
cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with either knockdown or overexpression of ADAR, and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of multiple ADAR substrates. Together these data show that
8-azaadenosine and
8-chloroadenosine are not suitable small molecules for
therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors.