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Zunsemetinib (ATI-450; CDD-450) is a novel and potent inhibitor of p38α mitogen-activated protein kinase-activated protein kinase 2 (MK2) with the potential to be used for immuno-inflammatory disease.
ln Vitro |
While zunsemetinib (1 and 10 μM; 1 hour; WT and NOM ID BMM) has no effect on NLRP3 expression, it promotes the degradation of IL-1β mRNA, which lowers the expression of IL-1β [1]. Zunsemetinib (0.4 nM~1 μM; 16 hours; PBMC) increases the instability of IL-1β mRNA and decreases the production of IL-1β [1]. Zunsemetinib preserves the p38α activation of other effectors including PRAK and ATF2, but specifically prevents the proinflammatory kinase MK2 from being activated by p38α MAPK. In vitro, RANKL-induced osteoclast production is inhibited by zunsemetinib [1].
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ln Vivo |
Zunsemetinib (1,000 ppm; oral) inhibits LPS-induced TNF-α expression for up to 4 weeks after dosing [1]. Zunsemetinib (10 and 20 mg/kg; oral) enhances bone mineral density [1]. Zunsemetinib reduces osteopenia in NOM IDc mice by suppressing osteoclastogenesis [1].
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Cell Assay |
RT-PCR[1]
Cell Types: WT and NOM ID BMM Tested Concentrations: 1 and 10 μM Incubation Duration: 1 hour Experimental Results: No effect on NLRP3 expression, but diminished IL-1β expression by promoting IL-1β mRNA degradation. |
Animal Protocol |
Animal/Disease Models: 8weeks old WT female mice [1]
Doses: 1,000 ppm Route of Administration: Oral Experimental Results: LPS-induced blockade of TNF-α expression persisted for up to 4 weeks after administration. Animal/Disease Models: Rat[1] Doses: 10 and 20 mg/kg Route of Administration: Oral Experimental Results:Increased bone density. |
References |
[1]. Zunsemetinib (ATI-450) – Investigational oral MK2 pathway inhibitor
[2]. Aclaris Therapeutics Announces ATI-450 (MK2 pathway Inhibitor) publication in Journal of Experimental Medicine [3]. Wang C, et al. Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. J Exp Med. 2018;215(5):1315-1325. |
Molecular Formula |
C25H22CLF2N5O3
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Molecular Weight |
513.9298
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Exact Mass |
513.1379
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Elemental Analysis |
C, 58.43; H, 4.31; Cl, 6.90; F, 7.39; N, 13.63; O, 9.34
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CAS # |
1640282-42-3
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Related CAS # |
(R)-Zunsemetinib;1640282-44-5
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Appearance |
Solid powder
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SMILES |
O=C1C(Cl)=C(OCC2=NC=C(F)C=C2F)C=C(C)N1C3=CC(C4=NC(C(C)(O)C)=NC=C4)=NC=C3C
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InChi Key |
FQPQMJULRZINPV-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C25H22ClF2N5O3/c1-13-10-30-18(17-5-6-29-24(32-17)25(3,4)35)9-20(13)33-14(2)7-21(22(26)23(33)34)36-12-19-16(28)8-15(27)11-31-19/h5-11,35H,12H2,1-4H3
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Chemical Name |
(2'S)-3-Chloro-4-[(3,5-difluoro-2-pyridinyl)methoxy]-2'-[2-(1-hydroxy-1-methylethyl)-4-pyrimidinyl]-5',6-dimethyl[1(2H),4'-bipyridin]-2-one
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Synonyms |
(P)-ATI-450 ATI-450CDD-450ATI450CDD450ATI 450 CDD 450ZunsemetinibATI-450 P atropisomer
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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 |
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) |
DMSO : ~100 mg/mL (~194.58 mM)
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Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.9458 mL | 9.7290 mL | 19.4579 mL | |
5 mM | 0.3892 mL | 1.9458 mL | 3.8916 mL | |
10 mM | 0.1946 mL | 0.9729 mL | 1.9458 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.