Tunlametinib
Based on 1 Customer Validation
Tunlametinib is a highly selective, orally active MEK1/2 inhibitor (IC50=1.9 nM, MEK1). Tunlametinib blocks the RAS-RAF-MEK-ERK signaling pathway, arrests tumor cell cycle and promotes apoptosis. Tunlametinib potently inhibits the proliferation of RAS/RAF mutant cancer cells (such as BRAF V600E, KRAS G12C mutant cells). Tunlametinib shows synergistic anti-tumor effects with BRAF/KRASG12C/SHP2 inhibitors, Docetaxel (HY-B0011). Tunlametinib can be used to study targeted therapy for RAS/RAF mutation-driven malignancies (such as melanoma, colorectal cancer, and non-small cell lung cancer).
For research use only. We do not sell to patients.
- Purity : 99.53%
- CAS No.: 1801756-06-8
- Formula: C16H12F2IN3O3S
- Molecular Weight:491.25
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Storage: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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Biological Activity
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Chemical Information
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Solvent & Solubility
- Protocols
- Purity & Documentation
- References
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Help & FAQs
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Biological Activity
Description
IC50 & Target
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MEK1 |
MEK2 |
In Vitro
Tunlametinib inhibits the cell viability of BRAF/KRAS mutant cell lines: A375, Colo-829, HL-60 melanoma cells, COLO 205, HT-29 colon cancer cells, Calu-6, A549 lung cancer cells, with IC50 of 0.86 nM, 3.46 nM, 0.67 nM, 0.94 nM, 10.07 nM, 59.89 nM, respectively. Tunlametinib has no significant effect on RAS/RAF wild-type cells (H1975, MRC-5)[1].
Tunlametinib (1-9 nM; 48 h) dose-dependently increases the proportion of A375 cells in the G0/G1 phase and induces cell cycle arrest[1].
Tunlametinib (10-90 nM or 1-9 nM; 48 h) dose-dependently induces apoptosis in COLO 205 cells (10-90 nM), without significant induction effect on A375 cells (1-9 nM)[1].
Tunlametinib (0.1-100 nM; 48 h) dose-dependently reduces the level of phosphorylated ERK (p-ERK) in A375 cells with an IC50 of approximately 1.16 nM. Tunlametinib completely inhibits ERK phosphorylation at a concentration of 100 nM[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:A375 (BRAF V600E mutant melanoma)
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Concentration:1 nM, 3 nM, 9 nM
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Incubation Time:48 h
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Result:Dose-dependently increased the number of G0/G1 phase cells (from 50% to 70% of total population), indicating cell cycle arrest.
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Cell Line:A375 (BRAF V600E mutant melanoma) and COLO 205 (BRAF-mutated colon cancer cells)
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Concentration:1 nM, 3 nM, 9 nM for A375 treatment; 10 nM, 30 nM, 90 nM for COLO 205 treatment
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Incubation Time:48 h
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Result:Resulted the proportion of apoptosis cells within normal limits, suggesting no significant apoptosis-inducing effect on A375 cells.
Resulted the proportion of apoptosis of 35.1%, 38.4% and 46.6% after treated with 10, 30 and 90 nM, respectively.
In Vivo
Tunlametinib (3, 9 mg/kg; oral; once daily; 21 days) inhibits tumor growth in H1975 (BRAF/KRAS wild-type lung cancer) tumor-bearing model in female BALB/c nude mice[1].
Tunlametinib (1 mg/kg, oral; once daily; 30 days) inhibits tumor growth in BRAF-mutated colorectal cancer patient-derived xenograft (PDX) models (CR0004, CR0029, CR2179, CR6289) without causing significant changes in body weight[1].
Tunlametinib (0.25 mg/kg, 1-10 days; 0.125 mg/kg, 11-21 days; oral, once daily) combined with SHP099 (HY-100388) (I: 50 mg/kg, 1-10 days; II: 25 mg/kg, 10-21 days; oral; once every 2 days), synergistically inhibits tumor growth in the H358 (KRASG12C mutant lung cancer) tumor-bearing model[1].
Tunlametinib (1 mg/kg; oral; once daily; 21 days) combined with AMG 510 (HY-114277) (3 mg/kg; oral; once daily; 21 days), synergistically inhibits tumor growth in KRASG12C mutant tumor-bearing models[1].
Tunlametinib (1 mg/kg; oral; once daily; 10 days) combined with Vemurafenib (HY-12057) (25 mg/kg; oral; twice daily; 10 days), synergistically inhibits tumor growth in A375 (BRAF mutant melanoma) tumor-bearing models[1].
Tunlametinib (0.5 mg/kg; oral; twice daily or 3.5 mg/kg, twice weekly; for 4 weeks) combined with Docetaxel (HY-B0011) (I: 10 mg/kg in weeks 1-2, II: 7.5 mg/kg in week 3, III: 5 mg/kg in week 4; intravenous injection; once a week), synergistically inhibits tumor growth in Calu-6, H358, H441, and A549 (all RAS mutant lung cancer) tumor-bearing models[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female BALB/c nude mice (5-8 weeks old) with A375, HT-29, Calu-6 cell-derived xenograft (CDX) model, or CRC atient-derived xenograft (PDX)[1]
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Dosage:1, 3, 6 mg/kg for CDX model; 1 mg/kg (PO) for PDX model
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Administration:Oral administration, once daily, 21 days
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Result:Significantly inhibited tumor growth in a dose-dependent manner, with better inhibitory effect than that of AZD6244 (25 mg/kg, po, QD).
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 1801756-06-8
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Appearance Solid
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Molecular Weight 491.25
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Formula C16H12F2IN3O3S
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Color Off-white to light yellow
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SMILES
O=C(C1=CC2=C(C(F)=C1NC3=CC=C(C=C3F)I)N=CS2)NOCCO
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Synonyms
HL-085
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvent & Solubility
In Vitro:
DMSO : 100 mg/mL (203.56 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: ≥ 5 mg/mL (10.18 mM); Clear solution
This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 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: ≥ 5 mg/mL (10.18 mM); Clear solution
This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 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.
Protocols
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Apoptosis
Apoptosis, also called programmed cell death, is generally characterized by distinct morphological characteristics.
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TUNEL staining for apoptotic DNA fragmentation
TUNEL staining detects DNA strand breaks by using terminal deoxynucleotidyl transferase to add labeled nucleotides to exposed 3′-OH DNA termini, generating either microscopic staining in fixed cells or tissue sections, or fluorescence/cytometric signal in cell suspensions. TUNEL positivity reflects DNA fragmentation but should not be interpreted alone as definitive apoptosis, because TUNEL can also label necrotic, autolytic, mechanically damaged, or DNA-repair-associated DNA breaks.
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Flow cytometric DNA-content cell-cycle staining
Flow cytometric DNA-content cell-cycle staining measures the fluorescence intensity of DNA-bound fluorochromes in single cells or nuclei to estimate DNA content distributions, allowing assignment of populations to G0/G1, S, and G2/M phases by DNA histogram deconvolution. Propidium iodide (PI) intercalates into DNA, and PI fluorescence is proportional to cellular DNA content when staining is performed under conditions that make DNA accessible and minimize non-DNA signal. Cells with G2/M DNA content are expected to show approximately twice the fluorescence intensity of G0/G1 cells, while S-phase cells occupy intermediate fluorescence values. PI-based DNA-content analysis can also detect cells with fractional DNA content, often reported as sub-G1, when DNA fragmentation and extraction during staining reduce retained DNA signal in apoptotic cells. DAPI is an alternative DNA fluorochrome for univariate DNA-content analysis, while bivariate approaches combining DNA content with proliferation
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Annexin V plus membrane-impermeant dye apoptosis staining
Annexin V-based apoptosis assays rely on the detection of phosphatidylserine (PS) externalization from the inner leaflet of the plasma membrane to the outer leaflet, an early biochemical hallmark of apoptosis. Fluorescently labeled Annexin V binds PS in a calcium-dependent manner, enabling identification of early apoptotic cells by flow cytometry or fluorescence microscopy. When combined with a membrane-impermeant DNA-binding dye (e. g. , propidium iodide), this approach allows discrimination between viable (Annexin V−/dye−), early apoptotic (Annexin V+/dye−), and late apoptotic or necrotic (Annexin V+/dye+) cell populations by assessing membrane integrity and PS exposure.
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BrdU Incorporation Assay
Bromodeoxyuridine (BrdU) incorporation assay is based on the principle that BrdU, a thymidine analog, is incorporated into newly synthesized DNA during the S phase of the cell cycle, thereby serving as a marker of DNA replication and cellular proliferation. Incorporated BrdU can be detected using anti-BrdU antibodies following DNA denaturation, enabling visualization or quantification of proliferating cells through immunochemical detection methods such as immunofluorescence or immunohistochemistry.
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Apoptosis Solutions
Apoptosis is a regulated, generally non-lytic cell-death pathway that removes unwanted, damaged, infected, or abnormal cells through coordinated morphological changes, caspase activation, DNA fragmentation, and membrane remodeling. The intrinsic apoptosis pathway is controlled mainly by mitochondrial outer membrane permeabilization, BCL-2 family proteins, cytochrome c release, apoptosome formation, caspase-9 activation, and downstream executioner caspase-3/7 activation. The extrinsic apoptosis pathway is initiated by death receptors such as Fas, TNFR, and TRAIL receptors, which recruit adaptor proteins and activate caspase-8 before engaging executioner caspases or mitochondrial amplification through BID cleavage. Apoptosis is linked to many phenotypes, including cancer cell killing, tissue homeostasis, immune regulation, neurodegeneration, infection response, and treatment-induced cytotoxicity; unresolved questions include how apoptosis interacts with necroptosis, pyroptosis, ferroptos
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Protocol for Cell Cycle
Cell-cycle analysis by flow cytometry measures DNA content in single cells to estimate the fraction of cells in G0/G1, S, and G2/M phases. Propidium iodide intercalates into DNA, and after RNA removal with RNase, fluorescence intensity reflects cellular DNA content: 2N cells are assigned to G0/G1, cells between 2N and 4N to S phase, and 4N cells to G2/M. DNA-content analysis alone cannot reliably separate G0 from G1 or G2 from M. Ki-67 can distinguish quiescent G0 cells from cycling cells, EdU or BrdU incorporation marks active DNA synthesis in S phase, and phospho-histone H3 staining identifies mitotic cells within the 4N population.
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Genotoxicity/Mutagenicity Study
The bacterial reverse mutation assay detects point mutations that restore amino-acid prototrophy in auxotrophic Salmonella typhimurium or Escherichia coli tester strains; after exposure to a test article, mutagenic activity is read out as an increased number of revertant colonies on minimal agar compared with the vehicle control. The assay uses tester strains with different mutation targets so that base-substitution and frameshift mutagens can be detected, and testing is performed with and without exogenous mammalian metabolic activation because some chemicals require biotransformation to become mutagenic.
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Cell Viability Determination by MTT Colorimetric Assay
The following protocol uses the MTT colorimetric assay as a classic literature-established method for assessing cell viability/metabolic activity in cultured mammalian cells. MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] is reduced by metabolically active cells to a colored formazan product; the amount of formazan is quantified spectrophotometrically and provides an indirect measure of metabolically active viable cells. Importantly, MTT reduction reflects cellular oxidoreductase/metabolic activity rather than an absolute direct count of living cells, so changes in cellular metabolism can alter the signal independently of cell number.
Purity & Documentation
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Data Sheet (280 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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Handling Instructions (2659 KB)
References
[1]. Liu Y, et al. Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor. Front Pharmacol. 2023 Sep 21;14:1271268. [Content Brief]
[2]. Sari MHM, et al. Editorial: Advances in molecular and pharmacological mechanisms of novel targeted therapies for melanoma. Front Oncol. 2024 Apr 4;14:1403778. [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 |
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| DMSO | 1 mM | 2.0356 mL | 10.1781 mL | 20.3562 mL | 50.8906 mL |
| 5 mM | 0.4071 mL | 2.0356 mL | 4.0712 mL | 10.1781 mL | |
| 10 mM | 0.2036 mL | 1.0178 mL | 2.0356 mL | 5.0891 mL | |
| 15 mM | 0.1357 mL | 0.6785 mL | 1.3571 mL | 3.3927 mL | |
| 20 mM | 0.1018 mL | 0.5089 mL | 1.0178 mL | 2.5445 mL | |
| 25 mM | 0.0814 mL | 0.4071 mL | 0.8142 mL | 2.0356 mL | |
| 30 mM | 0.0679 mL | 0.3393 mL | 0.6785 mL | 1.6964 mL | |
| 40 mM | 0.0509 mL | 0.2545 mL | 0.5089 mL | 1.2723 mL | |
| 50 mM | 0.0407 mL | 0.2036 mL | 0.4071 mL | 1.0178 mL | |
| 60 mM | 0.0339 mL | 0.1696 mL | 0.3393 mL | 0.8482 mL | |
| 80 mM | 0.0254 mL | 0.1272 mL | 0.2545 mL | 0.6361 mL | |
| 100 mM | 0.0204 mL | 0.1018 mL | 0.2036 mL | 0.5089 mL |
Tunlametinib Related Classifications
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