产品号 #72982_C
MEK/ERK通路抑制剂；抑制B-RAF、B-RAFV600E和C-RAF-1
总览
AZ628是一种喹唑啉酮，可抑制多种快速加速纤维肉瘤（RAF）激酶，包括B-RAF、B-RAF V600E和C-RAF-1（体外激酶测定IC₅₀值分别为105、34和29 nM（ Khazak et al.）。它强烈促进B-Raf二聚化，作为一种紧密结合抑制剂，并表现出极慢的解离速率（Hatzivassiliou et al.; Lavoie et al.）。特异性分析显示，还可以抑制其他多种酪氨酸激酶的活化，包括激酶插入结构域受体（KDR）、盘状结构域受体2 （DDR2）、Lck/Yes Novel （LYN）、猫McDonough肉瘤（FMS）和FMS样酪氨酸激酶1 (FLT1) （Khazak et al.）。
癌症研究
·抑制肿瘤生长、诱导细胞周期阻滞和引起细胞凋亡，尤其是在B-RAF V600E突变的细胞系中效果显著（McDermott et al.; Khazak et al.）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
878739-06-1
化学式
C₂₇H₂₅N₅O₂
纯度
≥98%
通路
MEK/ERK
靶点
B-RAF，C-RAF
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 (4)
Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nature chemical biology 2013 JUL
Abstract
RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain.
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010
Abstract
Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proceedings of the National Academy of Sciences of the United States of America 2007
Abstract
Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were ineffective against unselected cell lines but exhibited dramatic cell killing of small nonoverlapping subsets. Cells with exquisite sensitivity to EGFR, HER2, MET, or BRAF kinase inhibitors were marked by activating mutations or amplification of the drug target. Although most cell lines recapitulated known tumor-associated genotypes, the screen revealed low-frequency drug-sensitizing genotypes in tumor types not previously associated with drug susceptibility. Furthermore, comparing drugs thought to target the same kinase revealed striking differences, predictive of clinical efficacy. Genetically defined cancer subsets, irrespective of tissue type, predict response to kinase inhibitors, and provide an important preclinical model to guide early clinical applications of novel targeted inhibitors.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 878739-06-1 |
| Chemical Formula | C₂₇H₂₅N₅O₂ |
| Purity | ≥ 98% |
| Target | B-RAF, C-RAF |
| Pathway | MEK/ERK |
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