2. Academic Validation
  3. Design, synthesis and biological evaluation of sphingosine-1-phosphate receptor 2 antagonists as potent 5-FU-resistance reversal agents for the treatment of colorectal cancer

Design, synthesis and biological evaluation of sphingosine-1-phosphate receptor 2 antagonists as potent 5-FU-resistance reversal agents for the treatment of colorectal cancer

  • Eur J Med Chem. 2021 Dec 5:225:113775. doi: 10.1016/j.ejmech.2021.113775.
Dongdong Luo 1,  Yuhang Zhang 2,  Shuang Yang 1,  Xiaochen Tian 1,  Yan Lv 1,  Zhikun Guo 3,  Xiaochun Liu 1,  Gaitian Han 1,  Shuai Liu 1,  Wenyu Wang 4,  Shuxiang Cui 3,  Xianjun Qu 5,  Shengbiao Wan 6
Affiliations

Affiliations

  • 1 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100034, China.
  • 3 Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: quxj@ccmu.edu.cn.
  • 6 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China. Electronic address: biaowan@ouc.edu.cn.
PMID: 34411894 DOI: 10.1016/j.ejmech.2021.113775
Abstract

5-Fluorouracil (5-FU) and its prodrugs are the essential clinical drugs for colorectal Cancer (CRC) treatment. However, the drug resistance of 5-FU has caused high mortality of CRC patients. Thus, it is urgent to develop reversal agents of 5-FU resistance. Sphingosine-1-phosphate receptor 2 (S1PR2) was proved to be a potential target for reversing 5-FU resistance, but the activity of known S1PR2 antagonists JTE-013 were weak in 5-FU-resistant cell lines. To develop more potent S1PR2 antagonists to treat 5-FU-resistant Cancer, a series of JTE-013 derivatives were designed and synthesized. The most promising compound 40 could markedly reverse the resistance in 5-FU-resistant HCT116 cells and 5-FU-resistant SW620 cells via inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). The key was that compound 40 with improved pharmacokinetic properties significantly increased the inhibitory rate of 5-FU in the SW620/5-FU cells xenograft model with no observable toxicity by inhibiting the expression of DPD in tumor and liver tissues. Altogether, these results suggest that compound 40 may be a promising drug candidate to reverse 5-FU resistance in the treatment of CRC.

Keywords

5-FU-Resistance; Colorectal cancer therapy; Mouse xenograft model; Pharmacokinetic properties; S1PR2 antagonists.

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