产品号 #73072_C
MEK/ERK通路抑制剂；抑制BRAF V600E
达拉非尼是一种可逆的，选择性，ATP竞争性的B-RAF抑制剂，对 B-RAF的V600E 突变体的抑制活性显著高于野生型 B-RAF 和 C-RAF，IC₅₀值分别为0.8, 3.2和5 nM (Laquerre等人；Menzies等人)。
癌症研究
·在表达 B-RAF的V600E突变体的细胞中，降低ERK磷酸化并抑制细胞增殖。在携带 B-RAF（V600E） 突变的人源性黑色素瘤和结肠癌小鼠异种移植模型中有效抑制肿瘤生长（Rheault 等人）。
疾病建模
·通过对小鼠中受体相互作用蛋白激酶3（RIP3）明显的纳摩尔抑制，减轻对乙酰氨基酚诱导的肝损伤（Li等人）。
癌症研究
·在表达 B-RAF的V600E突变体的细胞中，降低ERK磷酸化并抑制细胞增殖。在携带 B-RAF（V600E） 突变的人源性黑色素瘤和结肠癌小鼠异种移植模型中有效抑制肿瘤生长（Rheault 等人）。
疾病建模
·通过对小鼠中受体相互作用蛋白激酶3（RIP3）明显的纳摩尔抑制，减轻对乙酰氨基酚诱导的肝损伤（Li等人）。
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (2)
Publications (3)
The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell death & disease 2014
Abstract
Receptor-interacting protein (RIP)3 is a critical regulator of necroptosis and has been demonstrated to be associated with various diseases, suggesting that its inhibitors are promising in the clinic. However, there have been few RIP3 inhibitors reported as yet. B-Raf(V600E) inhibitors are an important anticancer drug class for metastatic melanoma therapy. In this study, we found that 6 B-Raf inhibitors could inhibit RIP3 enzymatic activity in vitro. Among them, dabrafenib showed the most potent inhibition on RIP3, which was achieved by its ATP-competitive binding to the enzyme. Dabrafenib displayed highly selective inhibition on RIP3 over RIP1, RIP2 and RIP5. Moreover, only dabrafenib rescued cells from RIP3-mediated necroptosis induced by the necroptosis-induced combinations, that is, tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand or Fas ligand plus Smac mimetic and the caspase inhibitor z-VAD. Dabrafenib decreased the RIP3-mediated Ser358 phosphorylation of mixed lineage kinase domain-like protein (MLKL) and disrupted the interaction between RIP3 and MLKL. Notably, RIP3 inhibition of dabrafenib appeared to be independent of its B-Raf inhibition. Dabrafenib was further revealed to prevent acetaminophen-induced necrosis in normal human hepatocytes, which is considered to be mediated by RIP3. In acetaminophen-overdosed mouse models, dabrafenib was found to apparently ease the acetaminophen-caused liver damage. The results indicate that the anticancer B-Raf(V600E) inhibitor dabrafenib is a RIP3 inhibitor, which could serve as a sharp tool for probing the RIP3 biology and as a potential preventive or therapeutic agent for RIP3-involved necroptosis-related diseases such as acetaminophen-induced liver damage.
Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS medicinal chemistry letters 2013 MAR
Abstract
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
Dabrafenib and its potential for the treatment of metastatic melanoma. Drug design, development and therapy 2012
Abstract
The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAF(mut)) protein in melanomas with BRAF(V600E) and BRAF(V600K) genotypes. BRAF(V600E) metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 1195765-45-7 |
| Chemical Formula | C₂₃H₂₀F₃N₅O₂S₂ |
| Purity | ≥ 98% |
| Target | B-RAF |
| Pathway | MEK/ERK |
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