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| Targets |
The primary target of Darizmetinib is MKK4 (mitogen-activated protein kinase kinase 4, also known as MEK4 or MAP2K4). MKK4 is a dual-specificity kinase that activates the JNK and p38 MAPK signaling pathways, which play important roles in cellular stress responses, inflammation, and apoptosis. Darizmetinib inhibits MKK4 with an IC50 of 0.02 µM. It is selective for MKK4 over JNK1, B-RAF, and MKK7, with IC50 values of 7.07, 11.46, and 14.97 µM, respectively. By selectively inhibiting MKK4, Darizmetinib modulates downstream JNK and p38 signaling pathways.
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| ln Vitro |
Darizmetinib is a potent and selective MKK4 inhibitor with an IC50 of 0.02 µM. It demonstrates selectivity for MKK4 over JNK1, B-RAF, and MKK7 (IC50s = 7.07, 11.46, and 14.97 µM, respectively). This selectivity profile suggests that Darizmetinib specifically targets MKK4 without significantly affecting other kinases in the MAPK pathway. The compound is supplied with a purity of ≥98% and is soluble in DMSO at ≥10 mg/mL.
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| ln Vivo |
In vivo, Darizmetinib (10 mg/kg) decreases hepatocyte apoptosis in a mouse model of liver damage. This demonstrates its potential to protect against liver injury by inhibiting MKK4-mediated apoptosis. The compound is being developed for applications in extensive oncological liver resections or transplantation of small liver grafts, where reducing hepatocyte apoptosis could improve outcomes. Its oral activity makes it suitable for convenient administration.
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| Enzyme Assay |
In vitro enzyme activity assays for Darizmetinib typically involve measuring its ability to inhibit MKK4 kinase activity. Recombinant MKK4 enzyme is incubated with its substrate in the presence of ATP and increasing concentrations of Darizmetinib. Kinase activity is measured by detecting phosphorylation of the substrate, and the IC50 is determined from the dose-response curve. The reported IC50 is 0.02 µM. Selectivity is confirmed by testing against a panel of other kinases, including JNK1, B-RAF, and MKK7.
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| Cell Assay |
Cellular assays for Darizmetinib involve treating cells with the compound and measuring inhibition of MKK4-mediated signaling. Readouts include phosphorylation of downstream targets such as JNK and p38, as well as cellular responses such as apoptosis. The compound's ability to decrease hepatocyte apoptosis has been demonstrated in a mouse model of liver damage. Its effects on cell proliferation and survival would be assessed in relevant cell lines.
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| Animal Protocol |
In vivo efficacy of Darizmetinib has been evaluated in a mouse model of liver damage, where 10 mg/kg of the compound decreased hepatocyte apoptosis. The compound is being developed for applications in extensive oncological liver resections or transplantation of small liver grafts. Efficacy endpoints would include reduction of hepatocyte apoptosis, preservation of liver function, and improved survival. The compound's oral activity makes it suitable for convenient administration.
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| ADME/Pharmacokinetics |
Darizmetinib has a molecular weight of 421.46 and a molecular formula of C21H17F2N5O3S. It is an orally active, potent, and selective MKK4 inhibitor. The compound is supplied with a purity of ≥98% and is soluble in DMSO at ≥10 mg/mL. It should be stored at -20°C. The compound is for research use only and is not intended for human therapeutic use.
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| Toxicity/Toxicokinetics |
No specific toxicity data is detailed for Darizmetinib in the provided literature. As a research compound, its safety profile would be an important consideration for in vivo applications. Potential toxicities could be related to its effects on MKK4-mediated JNK and p38 signaling pathways in various tissues. Standard preclinical safety studies would be required to evaluate its safety for potential therapeutic applications. The compound is for research use only and is not intended for human therapeutic use.
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| References | |
| Additional Infomation |
Darizmetinib is a small molecule drug. Its International Nonproprietary Name (INN) prefix "-tinib" indicates that darizmetinib is a tyrosine kinase inhibitor. The monoisotopic molecular weight of darizmetinib is 457.1 Da. Darizmetinib is an orally bioavailable mitogen-activated protein kinase (MAP) kinase 4 (MKK4; MAP2K4) inhibitor with potential hepatoprotective, proliferative, and liver regeneration effects. After oral administration, darizmetinib selectively targets, binds to, and inhibits MKK4 activity in hepatocytes. This allows the MKK7 and mitogen-activated protein kinase 8 (MAPK8; MAP2K1) proliferation-enhancing pathways to be activated, which in turn activate the transcription factor ATF2 and the ETS domain protein ELK1. This promotes hepatocyte proliferation, increases hepatocyte survival, and promotes liver regeneration after hepatectomy. This may help prevent liver failure, restore liver quality, and protect hepatocytes from death. MKK4 is a MAP2K and part of the stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling pathway, playing a crucial role in inhibiting cell proliferation and regulating hepatocyte regeneration. Inhibiting MKK4 can enhance the regenerative capacity of hepatocytes.
Darizmetinib (HRX215) is an orally active, potent, and selective inhibitor of MKK4. It inhibits MKK4 with an IC50 of 0.02 µM and is selective over JNK1, B-RAF, and MKK7. The compound decreases hepatocyte apoptosis in a mouse model of liver damage at 10 mg/kg. Darizmetinib is being developed for applications in extensive oncological liver resections or transplantation of small liver grafts. It has a molecular formula of C21H17F2N5O3S and a molecular weight of 421.46. |
| Molecular Formula |
C21H17F2N5O3S
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| Molecular Weight |
457.453189611435
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| Exact Mass |
457.102
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| CAS # |
2369583-33-3
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| PubChem CID |
139369660
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| Appearance |
White to off-white solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
32
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| Complexity |
761
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(CCC)(NC1C(=CC=C(C(C2=C3C=C(C=NC3=NN2)C2C=CN=CC=2)=O)C=1F)F)(=O)=O
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| InChi Key |
WBNMARNYIFMNEP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H17F2N5O3S/c1-2-9-32(30,31)28-19-16(22)4-3-14(17(19)23)20(29)18-15-10-13(11-25-21(15)27-26-18)12-5-7-24-8-6-12/h3-8,10-11,28H,2,9H2,1H3,(H,25,26,27)
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| Chemical Name |
N-[2,6-difluoro-3-(5-pyridin-4-yl-2H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]propane-1-sulfonamide
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| Synonyms |
Darizmetinib; HRX-0215; LN3348; HRX215; HRX0215; HRX 0215; 2369583-33-3; HRX-0215; N-(2,6-Difluoro-3-(5-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; LN3348;
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.1860 mL | 10.9302 mL | 21.8603 mL | |
| 5 mM | 0.4372 mL | 2.1860 mL | 4.3721 mL | |
| 10 mM | 0.2186 mL | 1.0930 mL | 2.1860 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.
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