The data described in this Revefenacin article show that RDEA is a highly potent and selective inhibitor of MEK activity through its interaction with MEK.Xray crystallographic analysis reveals that RDEA binds to an allosteric pocket adjacent to the ATP binding site, locking the enzyme in a catalytically inactive conformation.When bound to MEK, RDEA interacts directly with ATP, the activation loop, and other surrounding protein residues through both hydrogen bonding and hydrophobic interactions, resulting in significant affinity for the binding pocket.A, mouse plasma concentrations of RDEA in response to a mgkg dose and predicted response to. B, pharmacokineticpharmacodynamic study of RDEA.Western blot of pERK and total ERK from tumors collected from mice at the indicated time points in the mgkg dose group.Plasma MEK inhibitor levels of RDEA are Letermovir plotted against MEK inhibition in brain.One hundred percent pERK levels were determined in vehicletreated rats.However, this differential sensitivity was only seen in our hands under anchoragedependent conditions. Anchorageindependent growth in a semisolid medium showed no clear sensitivity differences in the cancer cell lines tested.Further studies will be necessary to explain the mechanistic basis for this differential sensitivity.However, it seems that growth on plates reduces or bypasses the need for MEK activity for cell proliferation in some cell lines.The twicedaily and every other day pharmacokinetics of RDEA were then modeled from this actual data set.Superimposition of these pharmacokinetic profiles illustrated that the degree of antitumor activity seen with RDEA in these human tumor xenografts is more likely to correlate with maintaining plasma levels of RDEA above, ngmL. This is consistent with findings that once RDEA dosing stopped, tumors rapidly regrew in mice harboring residual tumor mass.These data suggest that continuously inhibiting MEK activity in a patients tumor throughout the period between doses will be important to achieve and sustain antitumor efficacy.To assess the potential for brain penetration and activity, we compared the ability of RDEA to inhibit pERK levels in the brain, lung, and tumor tissues of tumorbearing mice and found at least that fold lower plasma levels of RDEA were required to inhibit of the pERK level in tumor versus brain.Testing of other MEK inhibitors, including PD, revealed little or no difference in brain, tumor, and lung penetration versus plasma for these other compounds. We have tested mouse MEK in vitro and in vivo and see no difference in affinity or inhibitory activity between the species. These experiments suggest that RDEA exhibits reduced potential for brainrelated side effects and may preferentially accumulate in tumor tissue.To ensure that comparable pERK suppression in tumors correlated with efficacy in vivo, we tested both compounds side by side in two day xenograft models.These data are consistent with the pERK suppression detected in tumors from the day dose experiment for both compounds and is also consistent with the comparable affinities for the MEK enzyme for these two compounds.The differences noted for these molecules give further weight to the notion that alterations in chemical structure with similar effects on affinity can differentially affect activity in vivo. In summary, RDEA is a highly potent and selective inhibitor of MEK whose encouraging preclinical pharmacology profile supported entry into development for the treatment of cancer.

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