CYM-5478

CYM-5478 is a potent and highly selective S1P2 agonist with an EC50 of 119 nM in a TGFα-shedding assay. CYM-5478 protects neural-derived cell lines against Cisplatin toxicity[1][2].

Signaling Pathways >> GPCR/G Protein >> LPL Receptor

Research Areas >> Neurological Disease

S1PR1:1690 nM (EC50)

S1PR2:119 nM (EC50)

S1PR3:1950 nM (EC50)

S1PR4:>10 μM (EC50)

S1PR5:>10 μM (IC50)

CYM-5478 activates S1P2 with an EC50 of 119 nM, has less than 25% efficacy and shows 10-fold lower potency against the other S1P receptor subtypes (EC50 of 1690 nM, 1950 nM, >10 μM, >10 μM for S1P1, S1P3, S1P4, S1P5, respectively)[1]. CYM-5478 (1, 10, 100, 1000, 10000 nM) induces a statistically significant increase in the viability of C6 cells in a dose dependent manner at concentrations above 100 nM under nutrient-deprivation stress produced by serum-starvation. This effect was absent in the presence of 10% fetal bovine serum[1]. CYM-5478 (10 μM) causes a statistically significant, 3-fold increase in the EC50 of Cisplatin-mediated reduction in the viability of C6 glioma cells. CYM-5478 also attenuated Cisplatin-induced caspase 3/7 activity[1]. CYM-5478 (10 μM) causes significantly attenuated the increase of ROS in C6 cells exposed to Cisplatin (20 μM; for 24 hours)[1]. CYM-5478 (20 μM) protects neural cells but not breast cancer cells against Cisplatin toxicity (C6 glioma cells: EC50=4.54 μM; GT1-7: EC50=17 μM; SK-N-BE2: EC50=7.44 μM; CLU188: EC50=5.54 μM)[2].

CYM-5478 (1 mg/kg/day; ip) protects against Cisplatin-mediated (3 mg/kg; i.p.; once a week for 3 week) ototoxicity in rats[2]. CYM-5478 (20 μM) treatment results in near-complete protection from cisplatin-mediated loss of neuromast viability. CYM-5478 protects against loss of hair cell viability in a zebrafish model for ototoxicity[2].

[1]. Deron R Herr, et al. Sphingosine 1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death: implications for otoprotective therapy. Sci Rep. 2016 Apr 15;6:24541.

[2]. Wei Wang, et al. Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment. Cancers (Basel). 2020 Jan 15;12(1):211.