MK-8353 (SCH900353)

MK-8353 is a potent and selective inhibitor of both active and inactive ERK1 and ERK2 kinases (IC50=20 and 7 nM, respectively). MK-8353 is not a potent inhibitor of human CYPs 1A2, 2C9, 2C19 or 2D6 but inhibits CYP 3A4 (pre-incubation) in vitro and shows inhibition of CYP 3A4 and 2C8 (IC50 = 1.7 & 3.5 μM), which can cause drug-drug interactions when co administered with drugs that are primarily metabolized by CYP 2C8 or 3A4. MK-8353 is a weak inhibitor of hERG current, producing 16% inhibition at 0.6 μM. The IC50 values for inhibiting cell prolifertion are 371, 51, and 23 nM in A2058, HT-29, and Colo-205 cells respectively. In addition to inhibiting the kinase activity of ERK, MK-8353 prevents the phosphorylation of ERK by MEK^[1]. MK-8353 demonstrates kinase selectivity over a 227-human kinase panel; no additional kinase in the panel is inhibited by more than 35% at the 0.1 μM concentration, and only 3 kinases (CLK2, FLT4, and Aurora B) are inhibited >50% at the 1.0 μM concentration^[2].

A2058 cells (1 × 10⁶ cells per 10-cm dish) were treated with increasing concentrations of MK-8353 (nM) for 24 hours. Whole cell lysates were subjected to immunoblot analysis.

The in vivo pharmacokinetics and metabolism of MK-8353 are evaluated in male CD1 mice, Sprague Dawley (SD) rats, guinea pigs, beagle dogs, and cynomologus monkeys. With the exception of monkeys, MK-8353 shows moderate clearance after IV administration in all species, with a half-life range of 1.3-2.8 hr and a mean residence time range of 1.5-4.0 hr. Acceptable oral bioavailability is seen in mice, rats and dogs (23-80%) but low oral bioavailability in monkeys (2%). The permeability observed in Caco-2 cells was high (135 nm/sec), suggesting that intestinal absorption and permeability in humans should also be high. The steady-state volume of distribution in mice, dogs and monkeys are in the range of 0.9-3.3 L/kg, while in rats it is 0.1 L/kg. MK-8353 displays anti-tumor efficacy in several BRAF-mutant models^[1].