MK-2894

MK-2894 is the result of years of optimization (see https://doi.org/10.1016/j.bmcl.2008.01.103 and https://doi.org/10.1124/jpet.107.134510 for details of earlier molecules) to find potent, selective, and non-toxic PTGER4 (aka EP4) inhibitors. MK-2984 is very potent (Ki < 1 nM; cAMP functional IC50 = 2.5 nM) and has exquisite selectivity against all other prostanoid receptors, making it an ideal tool compound. Note that MK-2984 does not come with a matched negative control from Blouin et. al's 2010 disclosure; instead, I recommend that experimenters compare MK-2984 against PTGER1 and/or PTGER3 antagonists, such as MF266-1 and MF266-3, which are reported in Clark et al. 2008, for cellular experiments. MF2266-1 and -3 could serve as useful orthogonal probes for validating that a given phenotype is specific to PTGER4 in the absence of a true negative control. MK-2984 shines especially as an in vivo probe, as it does not have the GI toxicity associated with earlier chemotypes--indeed, MK-2984 is safe up to 30 mg/kg/day, while the efficacious dose is just ~ 1 mg/kg in mice. MK-2984 is therefore the best available in vivo probe for PTGER4 inhibition.

MK-2894 shows excellent selectivity towards PTGER4 over other prostanoid receptors in in vitro assays and shows highly potent in-cell activity. However, the in-cell selectivity is under-explored and its cytotoxicity is not disclosed. Although the in vivo activity is good, the potential selectivity issue might be a concern when use it in model organism.