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| 25mg |
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Purity: ≥98%
Belvarafenib (GDC-5573, HM95573, RG6185) is a novel, potent and selective inhibitor of the RAF (Rapidly Accelerated Fibrosarcoma) family kinases, with IC50 values for B-RAF, B-RAFv600E, and C-RAF of 56 nM, 7 nM, and 5 nM, respectively. The MAPK pathway, which is frequently activated in human tumors and promotes tumor growth, was intended to be inhibited by the drug.
| Targets |
BRAF V600E (IC50 = 7 nM); CRAF (IC50 = 5 nM); B-Raf (IC50 = 56 nM)
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|---|---|
| ln Vitro |
Belvarafenib exhibits high selectivity toward BRAF mutant and CRAF kinases when biochemically analyzed for over 120 kinases. For the BRAFWT, BRAFV600E, and CRAF kinases, the half maximal inhibitory concentrations (IC50) of HM95573 are 41 nM, 7 nM, and 2 nM, respectively. It appears that CSF1R (44 nM), DDR1 (77 nM), and DDR2 (182 nM) are the next kinases to be severely inhibited after RAF kinases. Mutant melanoma cell lines for BRAF and NRAS, including A375 (IC50: 57 nM) and SK-MEL-28 (69 nM), as well as SK-MEL-2 (53 nM) and SK-MEL-30 (24 nM), both exhibit potent growth inhibition when treated with HM95573. In addition, treatment with HM95573 effectively inhibits the phosphorylations of MEK and ERK downstream kinases linked to cell proliferation in mutant BRAF and mutant NRAS melanoma cells. Even in the presence of HGF, which is known to be a mediator of innate resistance to RAF inhibitors, HM95573 inhibits downstream signaling in melanoma cells[1].
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| ln Vivo |
Belvarafenib shows the excellent antitumor activity in mouse models that were xenografted with cell lines that had both BRAF mutations (such as A375 and SK-MEL-28) and NRAS mutations (such as SK-MEL-2 and SK-MEL-30)[1].
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| Cell Assay |
For 48 hours, the pan-Raf inhibitor belvarafenib was used to treat SUM-159 cells.
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| References | |
| Additional Infomation |
Belvarafenib is an orally available inhibitor of members of the Raf family of serine/threonine protein kinases, with potential antineoplastic activity. Upon administration, belvarafenib binds to and inhibits the B-Raf mutant V600E and C-Raf. This inhibits B-Raf V600E- and C-Raf-mediated signal transduction pathways, thereby inhibiting tumor cell growth of susceptible tumor cells. In addition, belvarafenib may also inhibit mutated Ras proteins. Raf protein kinases play a key role in the Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which is often dysregulated in human cancers and plays a key role in tumor cell proliferation and survival. The Raf mutation B-Raf V600E, where the valine at residue 600 is substituted for glutamic acid, is frequently overexpressed in a variety of human tumors and results in the constitutive activation of the Raf/MEK/ERK signaling pathway.
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| Molecular Formula |
C23H16CLFN6OS
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|---|---|
| Molecular Weight |
478.9291
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| Exact Mass |
478.08
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| Elemental Analysis |
C, 57.68; H, 3.37; Cl, 7.40; F, 3.97; N, 17.55; O, 3.34; S, 6.69
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| CAS # |
1446113-23-0
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| Related CAS # |
Belvarafenib TFA;2443966-84-3
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| PubChem CID |
89655386
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| Appearance |
Off-white to yellow solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
708
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
KVCQTKNUUQOELD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H16ClFN6OS/c1-11-5-6-13-12(7-8-27-22(13)30-16-4-2-3-15(24)17(16)25)18(11)31-23(32)14-9-33-20-19(14)28-10-29-21(20)26/h2-10H,1H3,(H,27,30)(H,31,32)(H2,26,28,29)
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| Chemical Name |
4-amino-N-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide
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| Synonyms |
Belvarafenib; GDC-5573; GDC 5573; GDC5573; HM 95573; HM-95573; HM95573; RG-6185; RG 6185; RG6185
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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: 12.5~96 mg/mL (26.1~200.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0880 mL | 10.4399 mL | 20.8799 mL | |
| 5 mM | 0.4176 mL | 2.0880 mL | 4.1760 mL | |
| 10 mM | 0.2088 mL | 1.0440 mL | 2.0880 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04835805 | Recruiting | Drug: Belvarafenib Drug: Cobimetinib |
Melanoma | Genentech, Inc. | May 13, 2021 | Phase 1 |
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