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| 25mg |
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Purity: ≥98%
MK-8353 (also known as SCH900353; SCH-900353) is a novel, potent, selective and orally bioavailable ERK inhibitor with anticancer activity. It inhibited ERK1/2 with IC50 values of 23.0 nM and 8.8 nM, respectively, in an IMAP kinase assay, and an IC50 of 0.5 nM for nonactivated ERK2 in a MEK1-ERK2-coupled assay. In numerous preclinical cancer models, MK-8353 and SCH772984 showed comparable potency. Twenty-six patients were enrolled in the MK-8353-001 study and forty-eight patients were enrolled in the P07652 study. Diarrhoea (44%), fatigue (40%), nausea (32%), and rash (28%) were some of the negative effects. In the dose cohorts of 400 mg and 800 mg, dose-limiting toxicity was noted. Biological activity in preclinical data was found to be correlated with sufficient exposure to MK-8353. In the MK-8353-001 study, three out of fifteen patients with BRAFV600-mutant melanomas who were evaluable for treatment response showed partial response.
| Targets |
ERK2 (IC50 = 8.8 nM); ERK1 (IC50 = 23 nM)
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| ln Vitro |
MK-8353 is a potent and selective inhibitor of both active and dormant ERK1 and ERK2 kinases (IC50 = 20 and 7 nM, respectively). MK-8353 inhibits CYP 3A4 (pre-incubation) in vitro and exhibits 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. It does not inhibit human CYPs 1A2, 2C9, 2C19, or 2D6. At 0.6 μM, MK-8353 inhibits hERG current by 16%. In A2058, HT-29, and Colo-205 cells, the IC50 values for inhibiting cell prolifertion are 371, 51, and 23 nM, respectively. MK-8353 also stops MEK from phosphorylating ERK, in addition to inhibiting ERK's kinase activity[1]. MK-8353 exhibits kinase selectivity over a 227-human kinase panel; only 3 kinases (CLK2, FLT4, and Aurora B) are inhibited >50% at the 1.0 μM concentration.No other kinase in the panel is inhibited by more than 35% at the 0.1 μM concentration.
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| ln Vivo |
In male CD1 mice, Sprague Dawley (SD) rats, guinea pigs, beagle dogs, and cynomologus monkeys, the in vivo pharmacokinetics and metabolism of MK-8353 are examined. A half-life range of 1.3-2.8 hours and a mean residence time range of 1.5-4.0 hours are displayed by MK-8353 in all species, with the exception of monkeys, following IV administration. Dogs, mice, and rats all have a respectable oral bioavailability of between 23 and 80 percent, but monkeys have a low oral bioavailability of only 2%. Given the high (135 nm/sec) intestinal permeability and absorption seen in Caco-2 cells, it is likely that these parameters are also high in human beings. Rats have a steady-state volume of distribution that is 0.1 L/kg, whereas it ranges from 0.9 to 3.3 L/kg in mice, dogs, and monkeys. In numerous BRAF-mutant models, MK-8353 exhibits anti-tumor efficacy[1].
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| Cell Assay |
A2058 cells (1 × 106 cells per 10-cm dish) were given progressively higher doses of MK-8353 (nM) for 24 hours. Immunoblot analysis was conducted on whole cell lysates.
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| Animal Protocol |
Female athymic nude mice (inoculated with Colo-205 cancer cells) or SCID mice (inoculated with SK-MEL-28 melanoma cells)
30, 45 and 60 mg/kg p.o. |
| References |
| Molecular Formula |
C37H41N9O3S
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| Molecular Weight |
691.84
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| Exact Mass |
691.31
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| Elemental Analysis |
C, 64.23; H, 5.97; N, 18.22; O, 6.94; S, 4.63
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| CAS # |
1184173-73-6
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| Related CAS # |
1184173-73-6;1951448-73-9 (HCl);1951448-74-0 (HCl hydrate);1951428-60-6 (hydrate); 1951428-61-7 (x HCl);
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| Appearance |
Solid powder
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| SMILES |
CC(C)OC1=NC=C(C=C1)C2=NNC3=C2C=C(C=C3)NC(=O)[C@@]4(CCN(C4)CC(=O)N5CCC(=CC5)C6=CC=C(C=C6)C7=NN(C=N7)C)SC
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| InChi Key |
KPQQGHGDBBJGFA-QNGWXLTQSA-N
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| InChi Code |
InChI=1S/C37H41N9O3S/c1-24(2)49-32-12-9-28(20-38-32)34-30-19-29(10-11-31(30)41-42-34)40-36(48)37(50-4)15-18-45(22-37)21-33(47)46-16-13-26(14-17-46)25-5-7-27(8-6-25)35-39-23-44(3)43-35/h5-13,19-20,23-24H,14-18,21-22H2,1-4H3,(H,40,48)(H,41,42)/t37-/m0/s1
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| Chemical Name |
(3S)-3-methylsulfanyl-1-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-N-[3-(6-propan-2-yloxypyridin-3-yl)-1H-indazol-5-yl]pyrrolidine-3-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.01 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4454 mL | 7.2271 mL | 14.4542 mL | |
| 5 mM | 0.2891 mL | 1.4454 mL | 2.8908 mL | |
| 10 mM | 0.1445 mL | 0.7227 mL | 1.4454 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03745989 | Completed | Drug: MK-8353 Drug: Selumetinib |
Solid Tumors | Merck Sharp & Dohme LLC | February 22, 2019 | Phase 1 |
| NCT02972034 | Completed | Drug: MK-8353 Biological: Pembrolizumab |
Neoplasms Colorectal Cancer |
Merck Sharp & Dohme LLC | January 13, 2017 | Phase 1 |
| NCT01358331 | Terminated | Drug: MK-8353 | Tumor, Solid | Merck Sharp & Dohme LLC | November 4, 2011 | Phase 1 |
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Products are for research use only; We do not sell to patients
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