DataVXAdvanced SciencePaper
journal article·2026-07Open access

Molecular Glue cc‐885 Inhibits VHL‐Deficient Clear Cell Renal Cell Carcinoma via ETS1 Degradation

Taowei Yang, Qihao Li, Kun Ye, Kezhi Liu, Mi Zhou, Minyu Chen, Lican Liao, Kangbo Huang, Zhu Wang, Qiong Deng, Jieyan Wang, Meiyu Jin, Xu Chen, Hui Liang, Jiaxing Zhang, Junhang Luo

Advanced Science· Volume 13· Issue 42
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Source abstract

Abstract

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is a common and aggressive form of kidney cancer with VHL mutations present in > 50% of cases. These mutations lead to dysregulation of hypoxia‐inducible factors (HIFs) and activation of oncogenic pathways, making VHL‐deficient ccRCC a challenging target for therapy. In this study, we identified cc‐885, a molecular glue degrader, as a selective inhibitor of VHL‐deficient ccRCC. cc‐885 promotes ubiquitination and degradation of transcription factor ETS1, which cooperates with EPAS1 (HIF‐2α) to drive tumorigenesis. We demonstrated that cc‐885 selectively targeted the p51 and p42 isoforms of ETS1, disrupting p27/p51 balance and suppressing ETS1 transcriptional activity. Moreover, combining cc‐885 with an EPAS1 inhibitor, belzutifan, significantly enhanced the anti‐tumor efficacy. Our findings provide a novel and precise therapeutic strategy for VHL‐deficient ccRCC by targeting ETS1 degradation and disrupting the ETS1‐EPAS1 complex.
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Research context

OpenAlex topics: Cancer, Hypoxia, and Metabolism · Renal cell carcinoma treatment · Autophagy in Disease and Therapy

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong China

Department of Oncology and Southwest Cancer Center Southwest Hospital of Third Military Medical University (Army Medical University) Chongqing China

Department of Oncology The First Affiliated Hospital, Sun Yat‐Sen University Guangzhou Guangdong China

Department of Urology Sun Yat‐sen University Cancer center Guangzhou Guangdong China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center For Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong China

Department of Urology The People's Hospital of Longhua Shenzhen Guangdong China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province

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