Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11

Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic modality that induces protein degradation by recruiting E3 ligases. Most reported PROTACs recruit ubiquitously expressed E3 ligases, such as cereblon and the von Hippel-Lindau tumor suppressor. Of the additional 600 + E3 ligases, recruiting those with tissue-restricted expression is attractive for increasing the specificity of PROTACs. This work describes the first reported PROTAC that recruits the tissue-specific E3 ligase scaffolding protein MAGEA11. As an initial demonstration, bromodomain and extra-terminal domain (BET)-targeting PROTACs that recruit MAGEA11 were synthesized and screened in osteosarcoma U2OS cells, identifying lead compound 105B. 105B degrades BET proteins in U2OS cells (BRD4 DC₅₀ = 0.130 nM, D_max = 78%) and KYSE180 esophageal squamous cell carcinoma cell lines (DC₅₀ = 40 nM, D_max = 70%), but shows no degradation in non-cancerous HEK293T cells. Mechanistic studies confirmed 105B's dependence on the ubiquitin-proteasome system and MAGEA11 and HUWE1 expression. 105B decreased levels of BET-regulated gene products RUNX2 and KRT14; however, improvements are still necessary to affect selective cytotoxicity. This work reports the first example of a PROTAC that recruits a tissue-specific E3 ligase to enable cancer-restricted degradation of BET proteins and highlights the need for further development of MAGEA11-recruiting degraders.