2. Academic Validation
  3. Molecular hybridization strategy - discovery of 2,3-diarylpyrazine derivatives as potent Skp2 inhibitors with improved anti-tumor activity and enhanced cisplatin sensitivity

Molecular hybridization strategy - discovery of 2,3-diarylpyrazine derivatives as potent Skp2 inhibitors with improved anti-tumor activity and enhanced cisplatin sensitivity

  • Eur J Med Chem. 2025 Oct 5:295:117788. doi: 10.1016/j.ejmech.2025.117788.
Kaizhao Hu 1,  Kun Zhang 2,  Ruihao Chui 2,  Wenhui Qiu 2,  Peipei Miao 3,  Linlin Zhang 2,  Mengying Ding 2,  Qingjin Zhang 2,  Bing Zhao 4,  Xiao-Jing Shi 5,  Hong-Min Liu 6
Affiliations

Affiliations

  • 1 Laboratory Animal Center, Academy of Medical Sciences, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450052, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 Laboratory Animal Center, Academy of Medical Sciences, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450052, China.
  • 4 Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: zhaobing@zzu.edu.cn.
  • 5 Laboratory Animal Center, Academy of Medical Sciences, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450052, China. Electronic address: shixiaojing@zzu.edu.cn.
  • 6 Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: liuhm@zzu.edu.cn.
PMID: 40460720 DOI: 10.1016/j.ejmech.2025.117788
Abstract

S-phase kinase-associated protein 2 (Skp2) is the vital component of the Skp1-Cullin 1-F-box (SCF) E3 ubiquitin Ligase complex, which precisely regulates CDK inhibitors by coordinating with Cks1 and has been identified to be involved in the progression of many human malignancies. Inspired by our previous study, we designed novel 2,3-diarylpyrazine derivatives via molecular hybridization strategy to enhance Skp2-Cks1 inhibition. Compound 10h emerged as the most potent inhibitor, displaying an IC50 value of 0.38 μM against Skp2-Cks1 binding with 7.3- and 12.8-fold improvements over leads ZK-14i and HK-E35, respectively. Moreover, 10h demonstrated excellent anti-tumor activities against lung Cancer NCl-H1299 and esophageal Cancer KYSE-510 cells, inducing S-phase arrest and suppressing proliferation through targeting Skp2. Notably, 10h significantly increased the sensitivity of NCl-H1299 cells to cisplatin by suppressing the cell stemness. Overall, this study developed 10h as a potent Skp2 inhibitor and explored its effects on tumor treatment, especially in enhancing the efficacy of cisplatin during chemotherapy.

Keywords

Chemosensitivity; Inhibitors; Skp2; Ubiquitin E3 ligase.

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