Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists

Eur J Med Chem. 2022 Jan 5:227:113923. doi: 10.1016/j.ejmech.2021.113923.

Dongdong Luo ¹, Zhikun Guo ², Xuecui Zhao ¹, Lijuan Wu ¹, Xiaochun Liu ¹, Yingzhi Zhang ², Yuhang Zhang ³, Zirong Deng ¹, Xianjun Qu ³, Shuxiang Cui ⁴, Shengbiao Wan ⁵

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, 266003, Qingdao, China.
2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China.
3 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China.
4 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China. Electronic address: sxccui@ccmu.edu.cn.
5 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, 266003, Qingdao, China. Electronic address: biaowan@ouc.edu.cn.

PMID: 34688013 DOI: 10.1016/j.ejmech.2021.113923

Abstract

Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 Antagonist (K_D = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116^DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116^DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal Cancer therapy.

Keywords

5-FU-Resistance; Colorectal cancer; S1PR2 antagonists; Xenograft models.

Name
Email *

	Sorry, but the email address you supplied was invalid.