| 產(chǎn)品描述： | PLX8394 is an orally active inhibitor of serine/threonine-protein kinase B-Raf (BRAF) protein. PLX8394 can selectively bind to and inhibit the activity of both wild-type and mutated forms of BRAF, then inhibit the proliferation of tumor cells which express mutated forms of BRAF. PLX8394 appears to be effective against tumors that express multiple mutated forms of the kinase and may be an effective therapeutic agent for tumors that are resistant to other BRAF inhibitor therapies that are specific for the BRAF V600E mutant |
| 靶點(diǎn)： |
Raf |
| 體外研究： |
PLX8394 (>25 nM) effectively inhibits phosphorylation of ERK1/2 in PRT 3 and PRT 4 cells and in addition to parental cells at 10 nM. PLX8394 effectively reduces phosphorylation of retinoblastoma protein, cyclin D3/D1, and expression of cyclin A2 in parental cells and PRT 3/4 cells. PLX8394 inhibits ERK1/2 phosphorylation and the growth of vemurafenib-resistant cells harboring either a BRAF V600K/L505H double mutation or a transposon-induced, N-terminal truncated form of BRAF. PLX8394 significantly impairs tumor cell growth and suppresses MAPK signaling in LA cell lines expressing either endogenous V600E or non-V600 mutant forms of BRAF |
| 體內(nèi)研究： |
In mice H1755 xenograft tumors, PLX8394 (150 mg/kg/day) substantially suppresses tumor growth, tumor cell proliferation and MAPK pathway signaling without overt toxicity. PLX8394 combines with erlotinib yields plasma erlotinib concentrations of >1 μM |
| 細(xì)胞實(shí)驗(yàn)： |
Dissolvent: DMSO. For MTT assays, 2×103?cells are seeded in triplicate in 96 wells in their regular culture medium (containing PLX4720 for PRT lines). Next day, cells are washed twice with PBS and then the medium is replenished containing the indicated RAF inhibitor. Medium is changed 48 hours later and after a further 48 hours, 10 μL of 5 mg/mL MTT reagent is added to wells and incubated for three hours. Formazan crystals are then solubilized overnight with a 1:10 dilution of 0.1 M glycine (pH 10.5) in DMSO. Wells are then analyzed at 450 nM in a Multiskan Spectrum spectrophotometer. Results depicted are normalized to DMSO conditions and are a composite of three independent experiments. Error bars shown are representative of the standard error of mean (SEM). |
| 動(dòng)物實(shí)驗(yàn)： |
PLX8394 is dissolved in PEG 400 [20% (v/v)], TPGS [5% (v/v)], and water [75% (v/v)].H1755 tumor xenografts are generated by injection of 5×106 cells in a 50/50 mixture for matrigel and PBS into 6- to 8-wk-old female NOD/SCID mice. Mice are randomized to treatment groups once tumors reach an average size of 150 mm3. H1755 cells are s.c. implanted and allowed to grow to appr 200 mm3 (4 wk after implantation). Mice are then treated with vehicle, vemurafenib, or PLX8394 for 15 d. The vehicle for daily oral gavage is PEG 400 [20% (vol/vol)], tocopheryl polyethylene glycol succinate (TPGS) [5% (vol/vol)], water [75% (vol/vol)]. PLX8394 is dissolved in PEG 400 [20% (vol/vol)], TPGS [5% (vol/vol)], and water [75% (vol/vol)] and vortexed continuously throughout the dosing period. PLX8394 (p.o.) is given at a dose of 150 mg/kg/d |
| 參考文獻(xiàn)： |
1. Okimoto RA, et al. PreClinicalal efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13456-13461. 2. Basile KJ, et al. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014 May;27(3):479-484. |
| 溶解性： |
Soluble in DMSO |
| 保存條件： |
-20℃ |
| 配置溶液濃度參考： |
|
1mg |
5mg |
10mg |
| 1 mM |
1.843 ml |
9.216 ml |
18.432 ml |
| 5 mM |
0.369 ml |
1.843 ml |
3.686 ml |
| 10 mM |
0.184 ml |
0.922 ml |
1.843 ml |
| 50 mM |
0.037 ml |
0.184 ml |
0.369 ml |
|
| 注意： |
部分產(chǎn)品我司僅能提供部分信息，我司不保證所提供信息的權(quán)威性，僅供客戶參考交流研究之用。 |
上海工商
危險(xiǎn)品化學(xué)品經(jīng)營(yíng)許可證（不帶存儲(chǔ)）
營(yíng)業(yè)執(zhí)照(三證合一)
北京