Design, synthesis, and evaluation of JTE-013 derivatives as novel potent S1PR2 antagonists for recovering the sensitivity of colorectal cancer to 5-fluorouracil
Design, synthesis, and evaluation of JTE-013 derivatives as novel potent S1PR2 antagonists for recovering the sensitivity of colorectal cancer to 5-fluorouracil
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JTE-013衍生物的设计、合成和评估作为新型有效的S1PR2拮抗剂，用于恢复结直肠癌对5-氟尿嘧啶的敏感性
DOI：
10.1016/j.bioorg.2022.106318
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发表时间：
2022
影响因子：
5.1
通讯作者：
Shuxiang Cui
中科院分区：
文献类型：
--
作者：
Zhikun Guo;Shuai Zhang;Xiaochun Liu;Guangjian Zhao;Yingzhi Zhang;Dongdong Luo;Xuecui Zhao;Ximing Xu;Xianjun Qu;Lin Li;Shengbiao Wan;Shuxiang Cui
靶向 1-磷酸鞘氨醇受体 2 (S1PR2) 已被证明是逆转 5-氟尿嘧啶 (5-FU) 耐药性的一种有前景的策略。在这里，我们报告发现新型 JTE-013 衍生化合物 37 比 JTE-013 和之前报道的化合物 5 具有更有效的 S1PR2 拮抗剂，可以逆转 SW620/5-FU 和 HCT116DPD 细胞中的 5-FU 耐药性。化合物37 h可以有效结合S1PR2并降低其表达，从而导致JMJD3和二氢嘧啶脱氢酶（DPD）的表达降低，同时还增加H3K27me3的水平以减少5-FU的降解，从而增加其在SW620/5-FU、HCT116DPD和L02细胞中的胞内浓度。此外，化合物 37 对其他 S1PR 和正常结肠细胞系 NCM460 表现出良好的选择性。蛋白质印迹分析表明，化合物 37 可以消除 FBAL 刺激的 S1PR2 上调的 DPD 表达。重要的是，化合物 37 还表现出良好的代谢稳定性，半衰期 (t1/2) 为 7.9 小时。此外，化合物 37 显着增强了 SW620/5-FU 动物模型中 5-FU 的抗肿瘤功效。因此，基于 JTE-013 的衍生化合物37代表了一种有前途的先导化合物，可用于开发用于结直肠癌 (CRC) 治疗的新型 5-FU 敏化剂。
Targeting sphingosine-1-phosphate receptor 2 (S1PR2) has been proved as a promising strategy to reverse 5-fluorouracil (5-FU) resistance. Here, we report the discovery of the novel JTE-013 derivative compound37 has a more effective S1PR2 antagonist to reverse 5-FU resistance in SW620/5-FU and HCT116DPDcells than JTE-013 and previously reported compound5. Compound37 hcould effectively bind S1PR2 and reduce its expression, thus leading to decreased expression of JMJD3 and dihydropyrimidine dehydrogenase (DPD), while also increasing the level of H3K27me3 to decrease the degradation of 5-FU and thereby increase its intracellular concentration in SW620/5-FU, HCT116DPD, and L02 cells. Furthermore, compound37 hshowed good selectivity to other S1PRs and normal colon cell line NCM460. Western blot analysis demonstrated that compound37 hcould abrogate the FBAL-stimulated upregulation of DPD expression by S1PR2. Importantly, compound37 halso showed favorable metabolic stability with a long half-life (t1/2) of 7.9 h. Moreover, compound37 hsignificantly enhanced the antitumor efficacy of 5-FU in the SW620/5-FU animal model. Thus, the JTE-013-based derivative compound37 hrepresents a promising lead compound for the development of novel 5-FU sensitizers for colorectal cancer (CRC) therapy.