Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer

  • J Med Chem. 2022 Nov 10;65(21):14553-14577. doi: 10.1021/acs.jmedchem.2c00958.
Dongdong Luo  1 ,  Xiaochun Liu  1 ,  Leilei Jiang  1 ,  Zhikun Guo  2 ,  Yan Lv  1 ,  Xiaochen Tian  1 ,  Xiaoyan Wang  1 ,  Shuxiang Cui  2 ,  Shengbiao Wan  1 ,  Xianjun Qu  3 ,  Ximing Xu  1 ,  Xiaoyang Li  1
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, 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.
PMID: 36269639 DOI: 10.1021/acs.jmedchem.2c00958
Abstract

Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal Cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound 43 potently interacts with S1PR2 with a KD value of 0.73 nM. It displays potent 5-FU resensitizing activity in multiple 5-FU-resistant tumor cell lines, particularly in SW620/5-FU (EC50 = 1.99 ± 0.03 μM) but shows no cytotoxicity in the normal colon cell line NCM460 up to 1000 μM. Moreover, 43 significantly enhances the antitumor efficacy of 5-FU in the SW620/5-FU animal model. These data suggest that 43 could be a novel lead compound for developing a 5-FU resensitizing agent.