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| 5mg |
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| 10mg |
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| 25mg |
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| Targets |
c-FMS (CSF-IR); c-Kit
Vimseltinib targets the colony-stimulating factor 1 receptor (CSF1R/c-FMS), a receptor tyrosine kinase that plays a critical role in the survival, proliferation, and differentiation of macrophages and other myeloid cells. It also inhibits c-Kit, another receptor tyrosine kinase involved in cell survival and proliferation. By inhibiting CSF1R and c-Kit, Vimseltinib modulates the tumor microenvironment and has anticancer and immunomodulatory effects. It inhibits CSF1R phosphorylated juxtamembrane domain (JMD) with an IC50 of 2.8 nM. |
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| ln Vitro |
Vimseltinib is a dual coupling drug for c-FMS (CSF-IR) and c-Kit that has anti-swelling and anticancer properties [1].
Vimseltinib is an orally bioavailable inhibitor of the tyrosine kinase receptor colony stimulating factor 1 receptor (CSF1R; CSF-1R; C-FMS; CD115; M-CSFR), with potential antineoplastic, macrophage checkpoint-inhibitory and immunomodulating activities. Upon administration, vimseltinib targets and binds to CSF1R expressed on monocytes, macrophages, and osteoclasts and inhibits the binding of the CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells. This blocks the production of inflammatory mediators by macrophages and monocytes and reduces inflammation. By blocking the recruitment to the tumor microenvironment (TME) and activity of CSF1R-dependent tumor-associated macrophages (TAMs), vimseltinib inhibits the immunomodulating activity by macrophages and enhances T-cell infiltration and anti-tumor T-cell immune responses, which inhibits the proliferation of tumor cells. TAMs play key roles in the TME and allow for immune suppression; TAMs promote inflammation, tumor cell proliferation, angiogenesis, invasiveness and survival. Vimseltinib exhibits potent in vitro activity as a CSF1R and c-Kit inhibitor. It has IC50 values of <0.01 μM for CSF1R (c-FMS) and 0.1-1 μM for c-Kit. It inhibits CSF1R phosphorylated juxtamembrane domain (JMD) with an IC50 of 2.8 nM, with 100-fold less potency against fully phosphorylated CSF1R (IC50=290 nM). The compound has anticancer and anti-proliferative activities. These in vitro activities confirm its potential for treating CSF1R-driven diseases. |
| ln Vivo |
In vivo, Vimseltinib has demonstrated efficacy in preclinical models of tenosynovial giant cell tumors (TGCT) and other CSF1R-driven diseases. As an orally active compound, it can be administered conveniently. It modulates the tumor microenvironment by inhibiting CSF1R, which is expected to reduce tumor-associated macrophage infiltration and promote antitumor immunity.
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| Enzyme Assay |
In vitro kinase assays for Vimseltinib involve measuring its inhibition of CSF1R and c-Kit kinase activity. These assays use recombinant CSF1R or c-Kit and a peptide substrate. The enzyme is incubated with the substrate and ATP in the presence of varying concentrations of Vimseltinib. The phosphorylation of the substrate is measured to determine the IC50 values. Selectivity profiling against a panel of kinases is performed to confirm specificity.
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| Cell Assay |
In vitro cellular assays for Vimseltinib are conducted in CSF1R-dependent cell lines, such as macrophages or cancer cell lines. Cells are treated with the compound at various concentrations, and cell proliferation is measured using MTT or CellTiter-Glo assays. CSF1R phosphorylation is measured by Western blot or phospho-specific ELISA. The compound's effects on macrophage differentiation and function can be assessed by measuring cytokine production and surface marker expression.
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| Animal Protocol |
In vivo animal experiments with Vimseltinib are conducted in mouse xenograft models of tenosynovial giant cell tumors (TGCT) and other CSF1R-driven tumors. Tumor-bearing mice are administered Vimseltinib orally at various doses. Tumor growth is monitored, and tumor tissues are harvested for analysis of CSF1R phosphorylation, macrophage infiltration, and tumor cell proliferation. Pharmacodynamic studies are performed to confirm target engagement and modulation of the tumor microenvironment.
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| ADME/Pharmacokinetics |
Vimseltinib is an orally active compound with favorable pharmacokinetic properties. It has good oral bioavailability and is suitable for once-daily dosing. The compound's half-life and tissue distribution have been characterized in preclinical studies. Its pharmacokinetic profile supports its use in clinical studies for TGCT and other indications. The compound is typically stored at -20°C.
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| Toxicity/Toxicokinetics |
Vimseltinib has been evaluated for safety in preclinical studies. The compound is generally well-tolerated at therapeutic doses. Common adverse effects may include those related to CSF1R inhibition, such as fatigue and hepatotoxicity. The compound is intended for research use and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling this compound.
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| References | |
| Additional Infomation |
Vimseltinib is an orally bioavailable tyrosine kinase receptor colony-stimulating factor 1 receptor (CSF1R; CSF-1R; C-FMS; CD115; M-CSFR) inhibitor with potential anti-tumor, macrophage checkpoint inhibitory, and immunomodulatory activities. After administration, Vimseltinib targets and binds to CSF1R expressed on the surface of monocytes, macrophages, and osteoclasts, inhibiting the binding of CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells. This blocks the production of inflammatory mediators by macrophages and monocytes, thereby alleviating inflammation. Vimseltinib also inhibits tumor cell proliferation by blocking the recruitment and activity of CSF1R-dependent tumor-associated macrophages (TAMs) to the tumor microenvironment (TME), suppressing the immunomodulatory activity of macrophages, enhancing T cell infiltration and anti-tumor T cell immune responses. TAMs play a crucial role in TME and are involved in immunosuppression; TAMs promote inflammation, tumor cell proliferation, angiogenesis, invasion, and survival.
Drug Indications Treatment of giant cell tumor of the tendon sheath Vimseltinib (DCC-3014, Romvimza) is an oral, switch-control tyrosine kinase inhibitor that selectively inhibits CSF1R/c-FMS. It has IC50 values of <0.01 μM for CSF1R and 0.1-1 μM for c-Kit. The compound is used in studies related to tenosynovial giant cell tumors (TGCT) and has anticancer and immunomodulatory effects. It inhibits CSF1R JMD phosphorylation with an IC50 of 2.8 nM. |
| Molecular Formula |
C23H25N7O2
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|---|---|
| Molecular Weight |
431.490303754807
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| Exact Mass |
431.206
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| CAS # |
1628606-05-2
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| Related CAS # |
1628606-05-2;Vimseltinib HCl;
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| PubChem CID |
86267612
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C1C=CN=C(C=1)C1C=NN(C)C=1)C1C=CC(C2=CN=C(N(C)C2=O)NC(C)C)=NC=1C
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| InChi Key |
TVGAHWWPABTBCX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H25N7O2/c1-14(2)27-23-25-12-18(22(31)30(23)5)19-6-7-21(15(3)28-19)32-17-8-9-24-20(10-17)16-11-26-29(4)13-16/h6-14H,1-5H3,(H,25,27)
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| Chemical Name |
2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one
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| Synonyms |
DCC3014; DCC 3014; Vimseltinib [INN]; Vimseltinib [USAN]; 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one;Vimseltinib; DCC-3014
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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 : ~50 mg/mL (~115.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.5 mg/mL (8.11 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 35.0 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: ≥ 3.5 mg/mL (8.11 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 35.0 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: ≥ 3.5 mg/mL (8.11 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 | 2.3176 mL | 11.5878 mL | 23.1755 mL | |
| 5 mM | 0.4635 mL | 2.3176 mL | 4.6351 mL | |
| 10 mM | 0.2318 mL | 1.1588 mL | 2.3176 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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