Targeting ADAR1 with a Novel Small-Molecule for the Treatment of Prostate Cancer

Abstract

Despite initial response to androgen signaling therapy, most prostate cancer (PCa) patients eventually relapse and remain incurable. ADAR1-mediated A-to-G editing plays oncogenic roles in various tumors. However, the specific function of ADAR1 and the global RNA edited targets governing PCa progression remain underexplored. Here, we demonstrate that highly expressed ADAR1 as a crucial oncogenic target in PCa, and develop a novel small-molecule ADAR1 inhibitor ZYS-1 with significant anti-tumor efficacy and favorable safety profile. Either depletion or pharmacological inhibition of ADAR1 dramatically suppress PCa growth, inhibit metastasis, and potentiate immune response. We further reveal that the translation of MTDH is repressed by ADAR1 in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, these results shed light on ADAR1 as a novel druggable target in PCa therapy and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.

ADAR Family Proteins: A Structural Review

“…Therefore, producing new ADAR modulators could potentially generate new drugs and therapies for many different fields. Known ADAR inhibitors include O-phenanthroline, a zinc chelator, and N-ethylmaleimide (NEM), an alkylating reagent, both inhibitors of hRED1 [156], ZYS-1, a new inhibitor of ADAR1 that shows promise as a therapeutic in prostate cancer [157], Rebecsinib, an inhibitor of splicing mediated ADAR1 activation [158], and 8-azanebularine which inhibits ADAR2 [159] (Figure 8). Also reported to inhibit ADAR1 is erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA) and compounds alendronate, etidronate, and zoledronate which inhibit the Zα domain of ADAR1p150 (Figure 8) [160,161].…”

“…There is a risk that in aiming to affect one disease target, another disease mechanism may be triggered. Recently, research in prostate cancer using the ADAR1 inhibitor, ZYS-1, has supported that ADARs can be druggable targets with favorable safety profiles, at least in the tested prostate cancer models [157]. Results so far support that ZYS-1 inhibition of ADAR1 can significantly reduce prostate cancer proliferation, invasion, and metastasis [154].…”