2. Academic Validation
  3. Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer

Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer

  • J Med Chem. 2020 May 14;63(9):4849-4866. doi: 10.1021/acs.jmedchem.0c00161.
Ze Dong 1,  Zhen Wang 1 2,  Zhong-Qiang Guo 3 4,  Shouzhe Gong 1,  Tao Zhang 1,  Jiang Liu 4,  Cheng Luo 1 5,  Hualiang Jiang 1 5 6,  Cai-Guang Yang 1 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Department of Urology, Zhongnan Hospital of Wuhan University, Hubei 430071, China.
  • 4 CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTec University, Shanghai 201210, China.
PMID: 32297747 DOI: 10.1021/acs.jmedchem.0c00161
Abstract

Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity Phosphatase 7, and decreased levels of phosphorylated Akt and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.

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