2. Academic Validation
  3. Discovery of 2-Pyrazolylpyrimidinone Derivatives as New SPOP Inhibitors for Renal Cell Carcinoma Therapy

Discovery of 2-Pyrazolylpyrimidinone Derivatives as New SPOP Inhibitors for Renal Cell Carcinoma Therapy

  • J Med Chem. 2025 Jul 24;68(14):14945-14961. doi: 10.1021/acs.jmedchem.5c00987.
Qiong Zhang 1 2,  Yangguo Zhou 1 2,  Jinglong Zhao 1 2,  Lvbin Hu 1 2,  Zhiwei Zhu 1 2,  Huifang Wang 1 2,  Yuhui Jin 1 2,  Qidong You 1 2,  Zhengyu Jiang 1 2,  Xiaoke Guo 1 2
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 40622869 DOI: 10.1021/acs.jmedchem.5c00987
Abstract

E3 Ligase speckle-type POZ protein (SPOP) is a potential therapeutic target in clear-cell renal cell carcinoma (ccRCC). However, small-molecule inhibitors targeting SPOP are rarely reported. Here, we identified DDO-4033 as a potent SPOP inhibitor through virtual screening and optimization. This 2-pyrazolylpyrimidinone derivative exhibited potent affinity with SPOP in vitro and efficiently impeded the malignant migration, invasion, and proliferation of ccRCC cell lines. DDO-4033 disrupted the SPOP recruitment of substrate LATS1 and inhibited the polyubiquitination and subsequent degradation, resulting in the upregulation of tumor suppressor LATS1. The increased abundance of LATS1 inactivated the transcriptional factors YAP1 and WWTR1/TAZ, ultimately turning on the Hippo signaling pathway in kidney Cancer cells. Our findings identify DDO-4033 as a new SPOP-targeted inhibitor with decent antitumor activity, providing a potential lead for the development of ccRCC therapy.

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