Quinn Sievers (@quinnsievers.bsky.social)

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. To this end, tissue-specific E3 ligases or E3 ligase-associated proteins that can be recruited for targeted protein degradation need to be identified. This work describes the first reported PROTAC that recruits the tissue-specific E3 ligase scaffolding protein MAGEA11. As an initial demonstration, a library of bromodomain and extra-terminal domain (BET)-targeting PROTACs that recruit MAGEA11 was synthesized. The library was screened in osteosarcoma U2OS cells, identifying lead compound 105B. 105B potently degrades BET proteins in U2OS osteosarcoma cell lines (BRD4 DC50 = 0.130 nM, Dmax = 78%) and KYSE180 esophageal squamous cell carcinoma cell lines (DC50 = 40 nM, Dmax = 70%), but shows no degradation in non-cancerous, MAGEA11-deficient HEK293T cells. Mechanistic studies confirmed 105B’s dependence on the ubiquitin-proteasome system and engagement of both MAGEA11 and BRD4. 105B decreased levels of BET-regulated gene products c-Myc, RUNX2, and KRT14; however, improvements are still necessary to affect selective cytotoxicity. This work reports the first example of a PROTAC recruiting a tissue-specific E3 ligase for cancer-restricted degradation of BET proteins and highlights the need for further development of MAGEA11-recruiting degraders. ### Competing Interest Statement The authors have declared no competing interest. * BCL-xL : B-cell lymphoma extra-large BET : Bromodomain and extra-terminal domain BD1, BD2 : Bromodomain 1, bromodomain 2 BRD2, BRD3, BRD4, BRDT : Bromodomain-containing proteins 2, 3, 4, and testis-specific (T) c-Myc : Myc proto-oncogene protein DC50 : Half-maximal degradation concentration DHFR : Dihydrofolate reductase Dmax : Maximum degradation achieved DMSO : Dimethyl sulfoxide E2F1 : E2F transcription factor 1 ESCC : Esophageal squamous cell carcinoma HER2 : Human epidermal growth factor receptor 2 HUWE1 : HECT, UBA, and WWE domain-containing E3 ubiquitin-protein ligase 1 IAP : Inhibitor of apoptosis protein Ki : Inhibition constant KRT14 : Keratin 14 MAGE : Melanoma antigen gene family MAGEA11 : Melanoma antigen family member A11 PEG : Polyethylene glycol PHOTAC : Photo-controllable proteolysis-targeting chimera PCF11 : Cleavage and polyadenylation factor 11 POI : Protein of interest PROTAC : Proteolysis-targeting chimera RUNX2 : Runt-related transcription factor 2 VHL : von Hippel–Lindau tumor suppressor protein National Institutes of Health, https://ror.org/01cwqze88, R35 GM140837-01, 5T32GM132029-06, T32GM008347 https://www.biorxiv.org/content/10.1101/2025.11.03.686228v1