M4K-2009
Based on 1 Customer Validation
M4K2009 is an orally active, blood-brain barrier permeable type I ALK2 inhibitor, with an IC50 value of 8-13 nM against human ALK2. M4K2009 exhibits moderate off-target inhibitory activity against hERG potassium channels (Potassium Channel), with an IC50 of 8 μM against the human channel. M4K2009 can be used in studies related to diffuse intrinsic pontine glioma.
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- Pureza : 99.35%
- No. CAS: 2600795-07-9
- Fòrmula: C25H29N3O3
- Peso molecular:419.52
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Almacenamiento:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Pureza y Documentación
- Referencias
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Help & FAQs
Actividad biológica
Descripciòn
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ALK2 8-13 nM (IC50) |
potassium channel 8 μM (IC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| HEK293 | IC50 |
12 nM
Compound: 6a; M4K2009
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Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 R206H mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 R206H mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
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[PMID: 32787083] |
| HEK293 | IC50 |
16 nM
Compound: 6a; M4K2009
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Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 G356D mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 G356D mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
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[PMID: 32787083] |
| HEK293 | IC50 |
2712 nM
Compound: 6a; M4K2009
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Inhibition of recombinant human ALK5 expressed in HEK293 cells transfected with CAGA-luciferase and Renilla luciferase reporter after 24 hrs by dual luciferase reporter assay
Inhibition of recombinant human ALK5 expressed in HEK293 cells transfected with CAGA-luciferase and Renilla luciferase reporter after 24 hrs by dual luciferase reporter assay
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[PMID: 32787083] |
| HEK293 | IC50 |
45 nM
Compound: 6a; M4K2009
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Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
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[PMID: 32787083] |
| HEK293 | IC50 |
6 nM
Compound: 6a; M4K2009
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Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 G328V mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 G328V mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
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[PMID: 32787083] |
| HEK293 | IC50 |
7 nM
Compound: 6a; M4K2009
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Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 Q207D mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
Competitive displacement of PBI-6908 from nanoluciferase-fused ALK2 Q207D mutant (unknown origin) expressed in HEK293 cells incubated for 2 hrs by NanoBRET NanoGlo substrate based NanoBRET assay
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[PMID: 32787083] |
| HEK293 | IC50 |
8.3 μM
Compound: 6a; M4K2009
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Inhibition of human ERG expressed in HEK293 cells after 5 mins by IonWorks barracuda patch clamp method
Inhibition of human ERG expressed in HEK293 cells after 5 mins by IonWorks barracuda patch clamp method
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[PMID: 32787083] |
In Vitro
M4K2009 (compound 6a) (1 μM) exhibits remarkable kinome-wide selectivity, with significant potency limited to DDR1, TNIK, and 6 other kinases at 1 μM[1].
M4K2009 potently inhibits recombinant wild-type and mutant ALK2 with IC50 values ranging from 8-13 nM, and shows high selectivity for ALK2 over ALK5 (187-fold), ALK3 (33-fold), and ALK4 (103-fold)[1].
M4K2009 (2 h) inhibits wild-type and mutant ALK2 in HEK-293 cells with cellular IC50 values ranging from 6-45 nM, and exhibits 60-fold cellular selectivity for ALK2 over ALK5[1].
M4K2009 (3-10 μM) shows greater than 100-fold selectivity for ALK2 over cannabinoid CB1 and adrenergic α2A receptors, and has a manageable hERG potassium channel inhibition profile with an IC50 of 8.3 μM[1].
M4K2009 (30 μM) does not significantly inhibit major human CYP enzyme isoforms at concentrations up to 30 μM[1].
M4K2009 (1 μM; 60 min) has moderate metabolic stability in mouse and human liver microsomes, high Cmax-2 permeability with minimal efflux, and a druglike plasma protein binding profile[1].
M4K2009 potently inhibits WT ALK2 with an IC50 of 13 nM, shows equipotent activity against ALK2G328V, ALK2R206H, and ALK2R258G mutants, and exhibits 141-fold selectivity for ALK2 over ALK5 in a radioactive in vitro biochemical kinase assay[2].
M4K2009 moderately inhibits the hERG potassium channel in HEK293 cells with an IC50 of 8 μM[2].
M4K2009 potently inhibits purified ALK2 with an IC50 of 13 nM and shows 187-fold selectivity over purified ALK5[4].
M4K2009 inhibits ALK2 activity in HEK-293 cells with an IC50 of 26 nM[4].
M4K2009 inhibits ALK5 activity in HEK-293 cells with an IC50 of 3297 nM and shows 126-fold cell-based selectivity for ALK2 over ALK5[4].
M4K2009 shows moderate metabolic stability in mouse liver microsomes, with 65% remaining after 60 min at 37 °C[4].
M4K2009 shows moderate metabolic stability in human liver microsomes, with 71% remaining after 60 min at 37 °C[4].
M4K2009 has high Caco-2 monolayer permeability with a Papp_AB of 5.4 × 10-6 cm/s and a low efflux ratio of 0.3[4].
M4K2009 potently inhibits the growth of ACVR1-mutant patient-derived DIPG cell lines SU-DIPG-XXI (GI50 = 52 nM) and HSJD-DIPG-007 (GI50 = 130 nM) and downregulates ID1 expression[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
In Vivo
M4K-2009 (25 mg/kg; p.o.; single administration) achieves high plasma exposure in healthy male NOD-SCID mice following a single oral dose of 25 mg/kg[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female CB17 SCID mice[1]
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Dosage:10 mg/kg; 100 mg/kg
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Administration:p.o.; single dose
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Result:Exhibited a dose-dependent increase in brain-to-plasma (B/P) ratios, which reached 0.90 at the dose of 10 mg/kg and 1.1 at 100 mg/kg.
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Animal Model:Male NOD-SCID mice[4]
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Dosage:25 mg/kg
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Administration:p.o.; single dose
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Result:Reached plasma concentration of 3021 nM at 0.5 h post-administration.
Reached plasma concentration of 4276 nM at 1 h post-administration.
Reached plasma concentration of 7489 nM at 2 h post-administration.
Reached plasma concentration of 13432 nM at 6 h post-administration.
Reached plasma concentration of 1542 nM at 24 h post-administration.
Chemical Information
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No. CAS 2600795-07-9
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Appearance Solid
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Peso molecular 419.52
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Fòrmula C25H29N3O3
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Color White to light yellow
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SMILES
COC(C=C1C2=CN=CC(C3=CC=C(N4CCNCC4)C=C3)=C2C)=C(C(OC)=C1)OC
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvente y solubilidad
In Vitro:
DMSO : 100 mg/mL (238.37 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
In Vivo:
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (5.96 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (5.96 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Pureza y Documentación
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Ficha de datos (278 KB)
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SDS (254 KB)
- English - EN (254 KB)
- Français - FR (254 KB)
- Deutsch - DE (254 KB)
- Norwegian - NO (254 KB)
- Español - ES (254 KB)
- Swedish - SV (254 KB)
- Italian - IT (254 KB)
- Korean - KR (254 KB)
- Portuguese - PT (254 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[1]. Smil D, et al. Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma. Journal of medicinal chemistry. 2020 Sep 10;63(17):10061-10085. [Content Brief]
[2]. Ensan D, et al. Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma. Journal of medicinal chemistry. 2020 May 14;63(9):4978-4996. [Content Brief]
[3]. Murrell E, et al. Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of C-Labeled ALK2 Inhibitors. ACS medicinal chemistry letters. 2021 May 13;12(5):846-850. [Content Brief]
[4]. González-Álvarez H, et al. Discovery of Conformationally Constrained ALK2 Inhibitors. Journal of medicinal chemistry. 2024 Mar 28;67(6):4707-4725. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 2.3837 mL | 11.9184 mL | 23.8368 mL | 59.5919 mL |
| 5 mM | 0.4767 mL | 2.3837 mL | 4.7674 mL | 11.9184 mL | |
| 10 mM | 0.2384 mL | 1.1918 mL | 2.3837 mL | 5.9592 mL | |
| 15 mM | 0.1589 mL | 0.7946 mL | 1.5891 mL | 3.9728 mL | |
| 20 mM | 0.1192 mL | 0.5959 mL | 1.1918 mL | 2.9796 mL | |
| 25 mM | 0.0953 mL | 0.4767 mL | 0.9535 mL | 2.3837 mL | |
| 30 mM | 0.0795 mL | 0.3973 mL | 0.7946 mL | 1.9864 mL | |
| 40 mM | 0.0596 mL | 0.2980 mL | 0.5959 mL | 1.4898 mL | |
| 50 mM | 0.0477 mL | 0.2384 mL | 0.4767 mL | 1.1918 mL | |
| 60 mM | 0.0397 mL | 0.1986 mL | 0.3973 mL | 0.9932 mL | |
| 80 mM | 0.0298 mL | 0.1490 mL | 0.2980 mL | 0.7449 mL | |
| 100 mM | 0.0238 mL | 0.1192 mL | 0.2384 mL | 0.5959 mL |
M4K-2009 Related Classifications
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