GID4招募PROTACs用于BRD4降解，克服CRBN和VHL缺乏引起的耐药性
GID4-Recruiting PROTACs for BRD4 Degradation Overcome Resistance Driven by CRBN and VHL Deficiency.
摘要(中文译文)
尽管已发现超过600种E3连接酶，目前的蛋白水解靶向嵌合体（PROTACs）主要依赖CRBN和VHL。近年来，GID4——CTLH E3连接酶复合物的底物受体——作为一种有前景的替代靶头而崭露头角。在此，通过对已知GID4配体的结构简化，我们开发了化合物作为一种强效的GID4招募型BRD4降解剂。该化合物通过泛素-蛋白酶体途径诱导了高效、选择性且GID4依赖性的BRD4降解（DC = 0.21 ± 0.04 μM）。关键的是，该化合物在VHL和CRBN缺陷模型中保持了降解活性，在VHL缺陷的786-O肾细胞癌（RCC）细胞中表现出更优的抗增殖效应。此外，该化合物在786-O异种移植模型中实现了显著的肿瘤生长抑制（TGI = 67%），优于相应的CRBN和VHL招募型类似物。该平台的更广泛用途通过成功降解VEGFR2得到进一步证实。总体而言，本研究确立了GID4作为一种可行的PROTAC靶头，在肾癌中具有治疗潜力。
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 as a potent GID4-recruiting BRD4 degrader. Compound induced efficient, selective, and GID4-dependent BRD4 degradation via the ubiquitin-proteasome pathway (DC = 0.21 ± 0.04 μM). Crucially, maintained degradation activity in VHL- and CRBN-deficient models, exhibiting superior antiproliferative effects in VHL-deficient 786-O renal cell carcinoma (RCC) cells. , 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.
如何引用
AMA
Yecheng Tang, Mingming Zhang, Yuxin Fang, Qingjun Li, Yingqi Song, Chunquan Sheng, et al. GID4-Recruiting PROTACs for BRD4 Degradation Overcome Resistance Driven by CRBN and VHL Deficiency.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c00367.
APA
Yecheng Tang, Mingming Zhang, Yuxin Fang, Qingjun Li, Yingqi Song, Chunquan Sheng, et al (2026). GID4-Recruiting PROTACs for BRD4 Degradation Overcome Resistance Driven by CRBN and VHL Deficiency.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c00367
GB/T 7714
Yecheng Tang, Mingming Zhang, Yuxin Fang, Qingjun Li, Yingqi Song, Chunquan Sheng, et al. GID4-Recruiting PROTACs for BRD4 Degradation Overcome Resistance Driven by CRBN and VHL Deficiency.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c00367.
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