Home MAPK ERK inhibitor MK-8353 (SCH900353)

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MK-8353 (SCH900353) ERK inhibitor

Cat.No.S8701

An orally bioavailable, selective, and potent ERK inhibitor, MK-8353 (SCH900353) 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).
MK-8353 (SCH900353) ERK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 691.84

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Quality Control

Batch: S870101 DMSO]50 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.92%
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99.92

Solubility

In vitro
Batch:

DMSO : 50 mg/mL (72.27 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 691.84 Formula

C37H41N9O3S

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1184173-73-6 -- Storage of Stock Solutions

Synonyms N/A Smiles CC(C)OC1=NC=C(C=C1)C2=NNC3=C2C=C(C=C3)NC(=O)C4(CCN(C4)CC(=O)N5CCC(=CC5)C6=CC=C(C=C6)C7=NN(C=N7)C)SC

Mechanism of Action

Targets/IC50/Ki
ERK2
(Cell-free assay)
7 nM
ERK1
(Cell-free assay)
20 nM
In vitro

MK-8353 (SCH900353) is a potent and selective inhibitor of both active and inactive ERK1 and ERK2 kinases (IC50=20 and 7 nM, respectively). It 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. This compound 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, it prevents the phosphorylation of ERK by MEK. It 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.
In vivo

The in vivo pharmacokinetics and metabolism of MK-8353 (SCH900353) are evaluated in male CD1 mice, Sprague Dawley (SD) rats, guinea pigs, beagle dogs, and cynomologus monkeys. With the exception of monkeys, it 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. This compound displays anti-tumor efficacy in several BRAF-mutant models.
References

Applications

Methods Biomarkers Images PMID
Western blot pERK / ERK / pRSK / RSK pERK / ERK / pRSK / RSK
S8701-WB1
29467321

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03745989 Completed
Solid Tumors
Merck Sharp & Dohme LLC
 February 22 2019 Phase 1

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