| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| Other Sizes |
| Targets |
Tinlorafenib specifically targets mutant forms of the serine/threonine-protein kinase B-Raf (BRAF), including the V600E and V600K mutations. These mutations, particularly V600E, lead to constitutive activation of the MAPK/ERK signaling pathway, driving uncontrolled cell proliferation in several cancers (e.g., melanoma, colorectal cancer, and brain tumors). By inhibiting these mutant kinases, Tinlorafenib blocks this oncogenic signaling cascade.
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| ln Vitro |
In vitro, Tinlorafenib potently inhibits BRAF V600E mutant kinase with an IC50 of 4.25 nM and BRAF V600K with an IC50 of 2.7 nM. It is highly selective for the mutant forms over wild-type BRAF. In cell-based assays, Tinlorafenib suppresses ERK phosphorylation and inhibits the proliferation of cancer cells harboring the BRAF V600E mutation, leading to G1 cell cycle arrest and induction of apoptosis.
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| ln Vivo |
In vivo, Tinlorafenib demonstrates robust anti-tumor activity. Its ability to cross the blood-brain barrier (brain-penetrant) is a key feature, as it allows for the treatment of brain tumors and brain metastases arising from BRAF-mutant cancers. In animal models, oral administration of Tinlorafenib leads to significant tumor regression in both subcutaneous and intracranial xenografts. It is being studied for CNS malignancies, which are difficult to treat due to poor penetration of many drugs.
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| Enzyme Assay |
For non-cell-based kinase inhibition assays, a standard HTRF (Homogeneous Time-Resolved Fluorescence) or mobility shift assay is used. Purified recombinant BRAF V600E or V600K kinase domains are incubated with a substrate (e.g., GST-MEK1) in the presence of ATP and varying concentrations of Tinlorafenib (0.001-10,000 nM). The reaction is stopped, and the degree of substrate phosphorylation is measured using a phospho-specific antibody. IC50 values are calculated from the dose-response curves.
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| Cell Assay |
For in vitro cell assays, human cancer cell lines harboring the BRAF V600E mutation are used (e.g., A375 melanoma cells, HT-29 colorectal cancer cells). Cells are seeded in 96-well plates and treated with a 3-fold dilution series of Tinlorafenib (0.1 nM - 10 microM) for 72 hours. Cell viability is assessed using the CellTiter-Glo luminescent assay. To confirm mechanism, A375 cells are treated with the compound for 4 hours, and lysates are analyzed by Western blot for p-MEK and p-ERK levels.
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| Animal Protocol |
For in vivo animal models, an orthotopic brain tumor model is used. Nude mice are intracranially implanted with BRAF V600E-mutant tumor cells (e.g., A375 melanoma cells or patient-derived xenograft cells). Mice are then randomized to receive Tinlorafenib orally once daily (e.g., 10-50 mg/kg) or vehicle. Tumor growth is monitored by bioluminescence imaging if the cells express luciferase. Survival is the primary endpoint. An efficacy study would show a significant increase in median survival time for treated mice.
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| ADME/Pharmacokinetics |
Tinlorafenib is an orally bioavailable, brain-penetrant inhibitor. Its ability to cross the blood-brain barrier (BBB) is characterized by a high brain-to-plasma ratio in preclinical species. Standard PK studies in rats or mice would show good oral bioavailability (e.g., >50%), low to moderate clearance, and a terminal half-life appropriate for once-daily dosing. The volume of distribution is likely large, reflecting extensive tissue distribution, including distribution to the CNS.
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| Toxicity/Toxicokinetics |
As an investigational drug, specific toxicology data for Tinlorafenib is limited in the public domain. Off-target toxicity is possible due to inhibition of wild-type RAF kinases, which are important for normal cell function. Class-based adverse events for BRAF inhibitors include arthralgia, rash, fatigue, and photosensitivity. Unlike first-generation BRAF inhibitors, Tinlorafenib is not reported to cause the paradoxical activation of the MAPK pathway in normal cells, which is a common side effect of older drugs (e.g., vemurafenib).
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| References | |
| Additional Infomation |
Tinlorafenib (PF-07284890) is a potent, selective, and highly penetrating small-molecule BRAF V600 mutant inhibitor. Tinlorafenib is an inhibitor of the BRAF (B-raf) protein and possesses potential antitumor activity. After administration, Tinlorafenib selectively targets, binds to, and inhibits BRAF activity, thereby inhibiting the proliferation of tumor cells expressing the mutant BRAF gene. BRAF is a serine/threonine protein kinase that plays a crucial role in regulating the MAP kinase/ERK signaling pathway, and BRAF gene mutations may lead to the persistent activation of this pathway. Tinlorafenib may cross the blood-brain barrier (BBB).
Tinlorafenib is an investigational new drug that has not yet received regulatory approval for clinical use. It is also known as PF-07284890 and ARRY-461. It is designed to overcome key limitations of first-generation BRAF inhibitors: poor CNS penetration and paradoxical activation of the MAPK pathway in non-mutant cells. By being brain-penetrant, it offers a therapeutic option for brain metastases, which are common in BRAF-mutant melanoma. Its unique binding mode may also provide activity against resistance mutations that arise to earlier BRAF inhibitors. |
| Molecular Formula |
C19H19CLF2N4O3S
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|---|---|
| Molecular Weight |
456.89
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| Exact Mass |
456.083
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| CAS # |
2573781-75-4
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| PubChem CID |
155434855
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
30
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| Complexity |
751
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(=CC=C2C(=C1C)C(N(C=N2)C)=O)NC1C(F)=CC=C(C=1Cl)NS(=O)(=O)CCCF
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| InChi Key |
VVLVISDSGRHLMB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H19ClF2N4O3S/c1-11-13(6-7-14-16(11)19(27)26(2)10-23-14)24-18-12(22)4-5-15(17(18)20)25-30(28,29)9-3-8-21/h4-7,10,24-25H,3,8-9H2,1-2H3
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| Chemical Name |
N-[2-chloro-3-[(3,5-dimethyl-4-oxoquinazolin-6-yl)amino]-4-fluorophenyl]-3-fluoropropane-1-sulfonamide
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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 : ~125 mg/mL (~273.59 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.55 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 (4.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1887 mL | 10.9436 mL | 21.8871 mL | |
| 5 mM | 0.4377 mL | 2.1887 mL | 4.3774 mL | |
| 10 mM | 0.2189 mL | 1.0944 mL | 2.1887 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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