Abstract C125: Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins

Targeted protein degradation using chimeric small molecules is an emerging modality in drug discovery. These compounds termed proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) contain two ligands connected with a linker: one ligand is specific for an E3 ubiquitin ligase, and the other ligand is specific for the target protein, and cross-link the E3 ligase and the target protein within the cell, thereby inducing the poly-ubiquitylation and proteasomal degradation of the target. Currently only a limited number of the E3 ligases, including IAPs, VHL and CRBN, can be recruited to the target proteins by this technology. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand for E3 ubiquitin ligase, we developed a novel class of chimeric molecules that recruit the aryl-hydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. We also developed a chimeric compound b-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using b-NF as an AhR ligand. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to recruit AhR E3 ligase to the target proteins. Citation Format: Nobumichi Ohoka, Genichiro Tsuji, Takuji Shoda, Takuma Fujisato, Masaaki Kurihara, Yosuke Demizu, Mikihiko Naito. Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C125. doi:10.1158/1535-7163.TARG-19-C125