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

  • J Med Chem. 2026 Jul 23;69(14):16704-16721. doi: 10.1021/acs.jmedchem.6c00367.
Yecheng Tang  1  2 ,  Mingming Zhang  3 ,  Yuxin Fang  2 ,  Qingjun Li  4 ,  Yingqi Song  4 ,  Chunquan Sheng  1  2 ,  Guoqiang Dong  2
Affiliations
  • 1. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China.
  • 2. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China.
  • 3. School of Pharmacy, Wannan Medical University, Wuhu 241002, China.
  • 4. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
PMID: 42402035 DOI: 10.1021/acs.jmedchem.6c00367
Abstract

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.

Products