MK-8353 (SCH900353)

Catalog No.S8701

MK-8353 (SCH900353) Chemical Structure

Molecular Weight(MW): 691.84

MK-8353 (SCH900353) is an orally bioavailable, selective, and potent ERK inhibitor that inhibits activated ERK1 and ERK2 in vitro, with IC50 values of 23.0 nM and 8.8 nM, respectively (IMAP kinase assay), and nonactivated ERK2, with an IC50 of 0.5 nM (MEK1-ERK2-coupled assay).

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Biological Activity

Description MK-8353 (SCH900353) is an orally bioavailable, selective, and potent ERK inhibitor that inhibits activated ERK1 and ERK2 in vitro, with IC50 values of 23.0 nM and 8.8 nM, respectively (IMAP kinase assay), and nonactivated ERK2, with an IC50 of 0.5 nM (MEK1-ERK2-coupled assay).
Targets
ERK2 [1]
(Cell-free assay)
ERK1 [1]
(Cell-free assay)
7 nM 20 nM
In vitro

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].

Assay
Methods Test Index PMID
Western blot
pERK / ERK / pRSK / RSK ; 

PubMed: 29467321     


MK-8353 inhibits ERK and RSK phosphorylation. 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 using antibodies described in the Methods section. Image shows a representative immunoblot of a total of two experiments.

pERK / ERK / pRSK / RSK ; 

PubMed: 29467321     


MK-8353 inhibits ERK and RSK phosphorylation. A2058 cells were treated with increasing concentrations of MK-8353 (nM) for 24 hours. Whole cell lysates were subjected to immunoblot analysis using antibodies described in the Methods section. Image shows a representative immunoblot of a total of two experiments.

29467321
In vivo

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].

Protocol

Cell Research:

[1]

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  • Cell lines: A2058 cells
  • Concentrations: 0, 3, 10, 30, 100, 300 nM
  • Incubation Time: 24 hours
  • Method:

    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.


    (Only for Reference)
Animal Research:

[2]

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  • Animal Models: Female athymic nude mice (inoculated with Colo-205 cancer cells) or SCID mice (inoculated with SK-MEL-28 melanoma cells)
  • Formulation: 20% HPBCD
  • Dosages: 30, 45 and 60 mg/kg
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 50 mg/mL (72.27 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 691.84
Formula

C37H41N9O3S

CAS No. 1184173-73-6
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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ERK Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID