S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer

[Display omitted] •S1PR2 is the potential upstream regulator of DPD expression in CRC cells.•JTE-013 effectively reversed 5-FU resistance of CRC both in vivo and in vitro.•JTE-013 levels off DPD-catalyzed degradation of intracellular 5-FU in CRC. In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with the in vivo HCT116DPD cells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01%–75.87%. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into α-fluoro-β-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs. This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.