GID4-Recruiting PROTACs for BRD4 Degradation Overcome Resistance Driven by CRBN and VHL Deficiency

Despite the identification of over 600 E3 ligases, current proteolysis-targeting chimeras (PROTACs) predominantly rely on CRBN and VHL. Recently, GID4, a substrate receptor of the CTLH E3 ligase complex, emerged as a promising alternative handle. Herein, through structural simplification of a known GID4 ligand, we developed compound a11 as a potent GID4-recruiting BRD4 degrader. Compound a11 induced efficient, selective, and GID4-dependent BRD4 degradation via the ubiquitin-proteasome pathway (DC₅₀ = 0.21 ± 0.04 μM). Crucially, a11 maintained degradation activity in VHL- and CRBN-deficient models, exhibiting superior antiproliferative effects in VHL-deficient 786-O renal cell carcinoma (RCC) cells. In vivo, a11 achieved significant tumor growth inhibition (TGI = 67%) in a 786-O xenograft model, outperforming corresponding CRBN- and VHL-recruiting analogs. This platform's broader utility was further confirmed by successfully degrading VEGFR2. Overall, this study establishes GID4 as a viable PROTAC handle with therapeutic potential in renal cancer.