MRK-740

MRK-740 is a probe that shows good biochemical target-based potency (80 nM), selectivity against other methyltransferases as well as against a customized panel of 108 enzymes and receptors at Eurofins Panlabs Discovery Services.  Moreover, it has also been shown to be sufficiently potent (0.8 uM) to be a useful probe to study the biology of PRMD9 in whole cells. The fact that a crystal structure of MRK-740 bound to PRMT9 is available that shows the mode of target engagement is a strong positive. On the other hand, because it shows cytotoxicity in HEK293 cells at 10 uM, as noted above this probe should not be used at concentrations above ~5 uM. It is unclear what the mechanism of cytotoxicity (both it and its inactive counterpart MRK-740-NC show similar off-target cytotoxicity). While the probe has a good drug-like structure, the methylpyridine structure suggests that it may inhibit kinase targets at higher concentrations, and since no broad kinase data has been published, this possibility has not been definitively ruled out. In addition, no pharmacokinetic data is available which should be generated independently if this probe is to be used in vivo.

MRK-740 is a highly selective probe without any significant off-targets in vitro or in cells with IC50 = 80 nM of cellular potency. We would recommend repeating the cytotoxicity assay in your relevant cell lines when you perform the experiment. It is important to also test the negative control in parallel as its observed cytotoxicity might be related to chemical structure, and not a target effect.