Abstract 1805: Identification of a small molecule that induces targeted protein degradation of ADAR1

Abstract Adenosine deaminase acting on RNA (ADAR) are a family of enzymes that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Recent evidence suggests that genetic deletion of ADAR1 render tumors cells substantially more vulnerable to immunotherapy. In cells, ADAR1 is expressed as two different isoforms, the constitutively expressed ADAR1p110 and the inducible ADAR1p150. Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in most tumors. Of note, many of the effects of ADAR1p150 appear to be independent of the protein’s RNA editing function suggesting that a small molecule which induces ADAR1p150 targeted protein degradation might be preferable to agents that simply block deaminase activity. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bind to the unique N-terminal region of ADAR1p150. One such molecule, CL-AD-100, directly bound to ADAR1p150 but not ADAR1p110. Moreover, sub-micromolar concentrations of CL-AD-100, induced proteasomal mediated degradation of ADAR1p150, without effecting ADAR1p110 expression. Cells treated with CL-AD-100 exhibited a signature consistent with what has been observed with ADAR1p150 genetic deletion, namely accumulation of dsRNA, an inflammatory gene expression profile and interferon-dependent cell death. These results therefore demonstrate the feasibility of generating a small molecule that induces the specific targeted protein degradation of ADAR1p150. Such a molecule should have wide applicability in ADAR1-addicted tumors, as well as more broadly, in immuno-oncology. Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Jason R. Kennerdell, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a small molecule that induces targeted protein degradation of ADAR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1805.