Belvarafenib
(Synonyms: HM95573; GDC-5573; RG6185) 目录号 : GC32950
An inhibitor of B-RAF and C-RAF
Cas No.:1446113-23-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Belvarafenib is an inhibitor of B-RAF and C-RAF (IC50s = 41, 7, and 2 nM for wild-type B-RAF, B-RAFV600E, and wild-type C-RAF, respectively).1 It is cytotoxic to B-RAFV600E-expressing A375 and SK-MEL-28 melanoma cells (IC50s = 57 and 69 nM, respectively), as well as COLO 205 and HCT116 colon and B-CPAP and CAL-62 thyroid cancer cells (IC50s = 116, 65, 43, and 479 nM, respectively). Belvarafenib reduces tumor growth in A375, SK-MEL-28, SK-MEL-2, and SK-MEL-30 mouse xenograft models.
1.Man, R.-J., Zhang, Y.-L., Jiang, A.-Q., et al.A patent review of RAF kinase inhibitors (2010-2018)Expert Opin. Ther. Pat.29(9)675-688(2019)
| Cas No. | 1446113-23-0 | SDF | |
| 别名 | HM95573; GDC-5573; RG6185 | ||
| Canonical SMILES | O=C(C(C1=NC=N2)=CSC1=C2N)NC(C3=C4C(NC(C=CC=C5Cl)=C5F)=NC=C3)=C(C=C4)C | ||
| 分子式 | C23H16ClFN6OS | 分子量 | 478.93 |
| 溶解度 | DMSO: 12.5 mg/mL (26.10 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.088 mL | 10.4399 mL | 20.8799 mL |
| 5 mM | 0.4176 mL | 2.088 mL | 4.176 mL |
| 10 mM | 0.2088 mL | 1.044 mL | 2.088 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
ARAF mutations confer resistance to the RAF inhibitor Belvarafenib in melanoma
Nature 2021 Jun;594(7863):418-423.PMID:33953400DOI:10.1038/s41586-021-03515-1.
Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of Belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with Belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to Belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.
Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model
Clin Exp Metastasis 2023 Feb 10.PMID:36763292DOI:10.1007/s10585-023-10198-7.
Brain metastasis is a common complication in melanoma patients with BRAF and NRAS mutations and has a poor prognosis. Although BRAF inhibitors are clinically approved, their poor brain penetration limits their efficacy in brain metastasis. Thus, melanoma brain metastasis still requires better treatment. Belvarafenib, a pan-RAF inhibitor, has reported antitumor activity in melanoma with RAF and RAS mutations in animal models and patients. However, brain permeability and antitumor efficacy on brain metastasis have not been determined. This study confirmed the brain penetration of Belvarafenib, the antitumor activity on BRAF and NRAS mutant melanoma, and the efficacy on melanoma within the brain. Belvarafenib strongly suppressed melanoma in BRAF V600E mutant A375SM tumor-bearing mice. It also significantly inhibited tumor growth in NRAS mutant SK-MEL-30 and K1735 tumor-bearing mice and synergized to enhance the antitumor activity combined with cobimetinib or atezolizumab. Belvarafenib was penetrated at considerable levels into the brains of mice and rats following oral administration. The exposure of Belvarafenib in the brain was similar to or higher than that in plasma, and this high brain penetration differed significantly from that of other BRAF inhibitors with low brain penetration. Most importantly, Belvarafenib strongly reduced tumor burden and markedly improved survival benefits in mice intracranially implanted with A375SM melanoma. These results demonstrated that Belvarafenib, which has favorable BBB permeability, and potent antitumor activity on the tumors with BRAF/NRAS mutations, may be a promising therapeutic option for patients with BRAF/NRAS mutant melanoma brain metastasis.
Melanoma with genetic alterations beyond the BRAFV600 mutation: management and new insights
Curr Opin Oncol 2022 Mar 1;34(2):115-122.PMID:35050937DOI:10.1097/CCO.0000000000000817.
Purpose of review: Molecular-targeted therapy with BRAF-/MEK-inhibitors has shown impressive activity in patients with advanced BRAFV600 mutant melanoma. In this review, we aim to summarize recent data and possible future therapeutic strategies involving small-molecule molecular-targeted therapies for advanced BRAFV600 wild-type melanoma. Recent findings: In patients with NRASQ61 mutant melanoma, downstream MEK-inhibition has shown some albeit low activity. MEK-inhibitors combined with novel RAF dimer inhibitors, such as Belvarafenib, or with CDK4/6-inhibitors have promising activity in NRAS mutant melanoma in early-phase trials. In patients with non-V600 BRAF mutant melanoma, MEK-inhibition with or without BRAF-inhibition appears to be effective, although large-scale prospective trials are lacking. As non-V600 BRAF mutants signal as dimers, novel RAF dimer inhibitors are also under investigation in this setting. MEK-inhibition is under investigation in NF1 mutant melanoma. Finally, in patients with BRAF/NRAS/NF1 wild-type melanoma, imatinib or nilotinib can be effective in cKIT mutant melanoma. Despite preclinical data suggesting synergistic activity, the combination of the MEK-inhibitor cobimetinib with the immune checkpoint inhibitor atezolizumab was not superior to the immune checkpoint inhibitor pembrolizumab. Summary: As of today, no molecular-targeted therapies have shown to improve survival in patients with advanced BRAFV600 wild-type melanoma. Combinatorial strategies, involving MEK-inhibitors, RAF dimer inhibitors and CDK4/6-inhibitors, are currently under investigation and have promising activity in advanced BRAFV600 wild-type melanoma.
ARAF Mutations Limit Response to RAF Dimer Inhibition
Cancer Discov 2021 Jul;11(7):1610.PMID:33990346DOI:10.1158/2159-8290.CD-RW2021-069.
Belvarafenib is active in BRAF- and NRAS-mutant tumors, but acquired ARAF mutations drive resistance.
Structure and RAF-family kinase isoform selectivity of Type II RAF inhibitors tovorafenib and naporafenib
J Biol Chem 2023 Mar 22;104634.PMID:36963492DOI:10.1016/j.jbc.2023.104634.
Upon activation by RAS, RAF-family kinases initiate signaling through the MAP kinase cascade to control cell growth, proliferation, and differentiation. Among RAF isoforms (ARAF, BRAF, and CRAF), oncogenic mutations are by far most frequent in BRAF. The BRAFV600E mutation drives more than half of all malignant melanoma and is also found in many other cancers. Selective inhibitors of BRAFV600E (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. By contrast, a number of "type II" RAF inhibitors have been developed as potent inhibitors of RAF dimers. Here we compare potency of type II inhibitors tovorafenib (TAK-580) and naporafenib (LHX254) in biochemical assays against the three RAF isoforms, and describe crystal structures of both compounds in complex with BRAF. We find that tovorafenib and naporafenib are most potent against CRAF, but markedly less potent against ARAF. Crystal structures of both compounds with BRAFV600E or WT BRAF reveal the details of their molecular interactions, including the expected type II binding mode, with full occupancy of both subunits of the BRAF dimer. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as Pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors Belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.