CYM-5541 (ML249) is an selective and allosteric S1P3 receptor agonist with an EC50 between 72 and 132 nM.
CYM-5541 is a full agonist, able to reach the maximum level of ERK phosphorylation that is observed with S1P. CYM-5541 has an EC50 of between 72 and 132 nM and exhibits exquisite selectivity over other S1P receptor subtypes: S1P1 EC50>10 μM, S1P2 EC50>50 μM, S1P4 EC50>50 μM, and S1P5 EC50>25 μM. CYM-5541 also shows selectivity over a large panel of protein targets, with no significant activities, in the Ricerca profiling panel of 55 GPCRs, ion channels, and transporters. CYM-5541 allowed us to identify an allosteric site where F263 is a key gate-keeper residue for its affinity and efficacy. The novel allosteric hydrophobic pocket may account for the S1P3 selectivity of CYM-5541[1].
References:
[1]. Jo E, et al. Novel selective allosteric and bitopic ligands for the S1P(3) receptor. ACS Chem Biol. 2012 Dec 21;7(12):1975-83.