RAF265 (CHIR-265)

目錄號：S2161 Purity: 99.97%

RAF265 (CHIR-265)是一種有效的選擇性C-Raf/B-Raf/B-Raf V600E抑制劑，IC50為3-60 nM，對VEGFR2磷酸化表現(xiàn)出有效的抑制作用，無細(xì)胞試驗中EC50為30 nM。RAF265 (CHIR-265)可誘導(dǎo)細(xì)胞周期阻滯和凋亡。Phase 2。

RAF265 (CHIR-265) Chemical Structure

CAS: 927880-90-8

規(guī)格	價格	庫存
10mM (1mL in DMSO)	1956.12	現(xiàn)貨
5mg	1415.74	現(xiàn)貨
10mg	2629.71	現(xiàn)貨
25mg	4561.83	現(xiàn)貨
100mg	13677.3	現(xiàn)貨
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產(chǎn)品質(zhì)控

批次：純度： 99.97%

99.97

RAF265 (CHIR-265)相關(guān)產(chǎn)品

相關(guān)靶點	C-Raf/Raf-1 B-Raf A-raf	點擊展開
相關(guān)產(chǎn)品	PLX-4720 LY3009120 AZ 628 GDC-0879 SB590885 TAK-632 GW5074 Avutometinib PLX7904 Plixorafenib (PLX8394) ZM 336372 Naporafenib (LXH254) Lifirafenib (BGB-283) Agerafenib (CEP-32496) Tovorafenib (MLN2480) Belvarafenib B-Raf inhibitor 1 (Compound 13) dihydrochloride RAF709 CCT196969	點擊展開
相關(guān)化合物庫	激酶抑制劑庫 MAPK抑制劑庫細(xì)胞周期化合物庫 TGF-beta/Smad信號通路庫抗阿爾茨海默病化合物庫	點擊展開

細(xì)胞實驗數(shù)據(jù)示例

細(xì)胞系	實驗類型	給藥濃度	孵育時間	活性描述	文獻(xiàn)信息
A375M	Function assay	100 mg/kg	48 hrs	Inhibition of B-RAF V600E mutant in mouse xenografted with human A375M cells assessed as reduction of phospho-MEK level in tumor at 100 mg/kg, po q24 after 48 hrs by Western blot analysis	26396681
A375M	Function assay	100 mg/kg	48 hrs	Inhibition of B-RAF V600E mutant in mouse xenografted with human A375M cells assessed as reduction of phospho-MEK level in tumor at 100 mg/kg, po q2d after 48 hrs by Western blot analysis	26396681
A375M	Function assay	30 to 100 mg/kg	4 hrs	Inhibition of B-RAF V600E mutant in mouse xenografted with human A375M cells assessed as reduction of phospho-MEK level in tumor at 30 to 100 mg/kg, po q2d measured after 4 hrs post-third dose by Western blot analysis	26396681
A375M	Antitumor assay	10 to 100 mg/kg	30 days	Antitumor activity against human A375M cells xenografted in mouse assessed as tumor regression at 10 to 100 mg/kg, po q2d measured up to 30 days	26396681
A375M	Function assay	100 mg/kg		fCmin in mouse xenografted with human A375M cells at 100 mg/kg, po q2d, fCmin=0.5μM.	26396681
VERO-E6	Function assay		48 hrs	Toxicity CC50 against VERO-E6 cells determined at 48 hours by high content imaging (same conditions as 2_LEY without exposure to 0.01 MOI SARS CoV-2 virus), CC50=9.19μM.	ChEMBL
VERO-E6	Function assay		48 hrs	Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging, IC50=14.64μM.	ChEMBL
A375	Function assay			Inhibition of B-RAF V600E mutant in human A375 cells assessed as phosphorylation of ERK, IC50=0.04μM.	26396681
A375M	Growth inhibition assay			Growth inhibition of A375M cells, IC50=0.14μM.	21576023
MALME-3M	Growth inhibition assay			Growth inhibition of MALME-3M cells, IC50=0.14μM.	21576023
SK-MEL-28	Growth inhibition assay			Growth inhibition of SK-MEL-28 cells, IC50=0.14μM.	21576023
Malme-3M	Function assay			Inhibition of B-RAF V600E mutant in human Malme-3M cells assessed as phosphorylation of ERK, IC50=0.04μM.	26396681
WM-1799	Function assay			Inhibition of B-RAF V600E mutant in human WM-1799 cells assessed as phosphorylation of ERK, IC50=0.04μM.	26396681
MALME-3M	Antiproliferative assay			Antiproliferative activity against human MALME-3M cells harboring B-RAF V600E mutant, IC50=0.04μM.	26396681
A375	Antiproliferative assay			Antiproliferative activity against human A375 cells harboring B-RAF V600E mutant, IC50=0.04μM.	26396681
WM1799	Antiproliferative assay			Antiproliferative activity against human WM1799 cells harboring B-RAF V600E mutant, IC50=0.04μM.	26396681
SK-MEL-28	Function assay			Inhibition of B-RAF V600E mutant in human SK-MEL-28 cells assessed as phosphorylation of ERK, IC50=0.14μM.	26396681
SK-MEL-28	Antiproliferative assay			Antiproliferative activity against human SK-MEL-28 cells harboring B-RAF V600E mutant, IC50=0.16μM.	26396681
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells	29435139
DAOY	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
SK-N-MC	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
BT-37	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
NB-EBc1	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
U-2 OS	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells	29435139
Saos-2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
SK-N-SH	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
NB1643	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells	29435139
LAN-5	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
BT-12	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
RD	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
NB1643	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells	29435139
SK-N-MC	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells	29435139
LAN-5	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for LAN-5 cells	29435139
NB-EBc1	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB-EBc1 cells	29435139
BT-37	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells	29435139
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells	29435139
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生物活性

產(chǎn)品描述

特性

CHIR-265是有效的c-Raf/B-Raf/mutB-Raf選擇性抑制劑，有效抑制含Ras/Raf 通路突變的腫瘤細(xì)胞增殖和存活,作用于一大批臨床前期模型具有高效性。

靶點

VEGFR2 ^[1] (Cell-free assay)	B-Raf ^[1] (Cell-free assay)
30 nM(EC50)	3 nM-60 nM

體外研究(In Vitro)
體外研究活性	RAF265 是有效的新型BRAF/VEGFR-2抑制劑, 作用于A375M(^V600EBRAF)人黑色素瘤細(xì)胞系，降低腫瘤糖代謝和FDG累積。RAF265抑制2-脫氧-2-[¹⁸F]氟代-D-葡萄糖(FDG)累積，這種作用存在劑量依賴性。 RAF265 顯著調(diào)節(jié)糖代謝, 嘧啶代謝,和凋亡通路。RAF265抑制VEGF誘導(dǎo)的血管生成和突變BRAF, 血管生成通路和新的用于血管生成成像的新興示蹤劑將被用于評估雙重作用機(jī)制的相對優(yōu)勢。^[1]RAF265作用于HT29和 MDAMB231 細(xì)胞中的BRAF，具有顯著活性，IC20為1到3 μM，IC50為5 到10 μM。使用濃度為1到10 μM RAF265 處理BRAF突變的細(xì)胞系，降低MEK磷酸化。 1 μM RAF265處理非 BRAF突變的細(xì)胞系，卻提高M(jìn)EK磷酸化, RAF265濃度達(dá)到 5 μM時可逆轉(zhuǎn)這種變化。加入RAD001，增強(qiáng)RAF265作用于 HCT116細(xì)胞系的毒性。^[2] RAF265處理，降低 pERK水平，這種作用存在劑量依賴性，0.5 mM RAF265 處理2小時后，完全阻斷 G2-M期進(jìn)展, 導(dǎo)致G2-M期細(xì)胞為0%。^[3] RAF265抑制表達(dá)^V600EBRAF的細(xì)胞生長，比作用于^WTBRAF細(xì)胞選擇性高14倍，比作用于對選擇性 BRAF抑制劑不敏感的守衛(wèi)-突變^T529N, ^V600EBRAF細(xì)胞高7倍, 說明RAF265的細(xì)胞內(nèi)靶點是BRAF。^[4]
激酶實驗	激酶組siRNA合成致死掃描和數(shù)據(jù)分析
激酶實驗	無血清培養(yǎng)基中的4 mL 206 nM siRNAs 加到每孔中, 0.03 mL DharmaFECT 1 在4 mL 無血清培養(yǎng)基中混合，加到每孔中，隨后在室溫下溫育30分鐘，形成脂質(zhì)/siRNA復(fù)合體。然后25 mL完全培養(yǎng)基中的1.5×10³ 細(xì)胞上樣到siRNA-脂質(zhì)復(fù)合體的頂端。每組反應(yīng)的siRNA終濃度為 25 nM。細(xì)胞在37^oC，含5% CO₂ 環(huán)境下溫育。siRNA轉(zhuǎn)染24小時后, 每孔中加入5 mL RAF265，使RAF265 終濃度變?yōu)?.4 mM。RAF265處理72小時后，通過CellTiter-Glo(CTG) 檢測實驗分析細(xì)胞活力，使用Envision獲得實驗數(shù)據(jù)。
細(xì)胞實驗	細(xì)胞系	A375M 人黑色素瘤細(xì)胞, 表達(dá)^V600EBRAF; MV4;11人急性髓細(xì)胞性白血病細(xì)胞,表達(dá)野生型 B-Raf
	濃度	0.1 到20 μM
	孵育時間	72小時
	方法	5×10⁴A375M 或MV4;11細(xì)胞接種在24孔板中過夜。更換培養(yǎng)基后, 在孔中加入1.0 μM RAF265, 0.1 μM RAF265, 或無藥劑(溶劑對照組)，重復(fù)三次，溫育 4到 5小時和24到28小時。加入 1 μCi FDG，溫育2小時。使用冷PBS沖洗細(xì)胞，然后使用 1 N NaOH溶解。使用Cobra II γ射線計數(shù)器測定一半樣本放射性。通過Bradford蛋白檢測實驗，使用剩余樣本測定蛋白濃度。在完全培養(yǎng)基中稀釋的RAF265，濃度為0.1 到20 μM，在96孔板中和細(xì)胞溫育，然后進(jìn)行細(xì)胞增殖檢測實驗。溫育72小時后，清洗細(xì)胞，進(jìn)行CellTiter-Glo檢測。

體內(nèi)研究(In Vivo)
體內(nèi)研究活性	RAF265 作用于A375M移植瘤，抑制 FDG累積。RAF265是新型，口服的小分子BRAF激酶和VEGFR-2抑制劑，作用于突變BRAF腫瘤模型，具有有效的抗癌活性。 ^[1]在人類移植瘤研究中, RAF265作用于突變BRAF人移植瘤和一些野生型BRAF模型，都具有高效性。^[4]
動物實驗	Animal Models	45只皮下注射3百萬A375M細(xì)胞的8周大的雌性nu/nu小鼠
	Dosages	100 mg/kg(體積約為 100 μL)
	Administration	口服處理，每兩天處理一次，持續(xù)14天。

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試驗信息 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT01352273	Completed	Advanced Solid Tumors	Array Biopharma now a wholly owned subsidiary of Pfizer\|Array BioPharma	June 2011	Phase 1

參考文獻(xiàn)
[1] AACR Meeting Abstracts 2008;2008:4876. [2] Mordant P, et al. Mol Cancer Ther, 2010, 9(2), 358-368. [3] Zitzmann K, et al. Endocr Relat Cancer, 2011, 18(2), 277-285. [4] Chen J, et al. Cancer Res, 2011, 71(12), 4280-4291. [5] Tseng JR, et al. Neoplasia, 2011, 13(3), 266-275. + 展開

參考文獻(xiàn)

[1] AACR Meeting Abstracts 2008;2008:4876.
[2] Mordant P, et al. Mol Cancer Ther, 2010, 9(2), 358-368.
[3] Zitzmann K, et al. Endocr Relat Cancer, 2011, 18(2), 277-285.

[4] Chen J, et al. Cancer Res, 2011, 71(12), 4280-4291.
[5] Tseng JR, et al. Neoplasia, 2011, 13(3), 266-275.

+ 展開

化學(xué)信息&溶解度

分子量	518.41	分子式	C₂₄H₁₆F₆N₆O
CAS號	927880-90-8	SDF	Download RAF265 (CHIR-265) SDF
Smiles	CN1C2=C(C=C(C=C2)OC3=CC(=NC=C3)C4=NC=C(N4)C(F)(F)F)N=C1NC5=CC=C(C=C5)C(F)(F)F
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復(fù)凍融！	1年-80°C溶于溶劑
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復(fù)凍融！	1個月-20°C溶于溶劑

體外溶解度
批次：

DMSO : 100 mg/mL ( (192.89 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO)

Ethanol : 45 mg/mL (86.8 mM)

Water : Insoluble

DMSO : 100 mg/mL ( (192.89 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO)

Ethanol : 50 mg/mL (96.44 mM)

Water : Insoluble

摩爾濃度計算器

體內(nèi)溶解度
批次：

現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑

動物體內(nèi)配方計算器

實驗計算

摩爾濃度計算器

質(zhì)量	濃度	體積	分子量
=	×	×

稀釋計算器分子量計算器

動物體內(nèi)配方計算器（澄清溶液）

第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）

給藥劑量 mg/kg 動物平均體重 g 每只動物給藥體積 μL 動物數(shù)量只

第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）

% DMSO + % + % Tween 80 + % ddH2O

%DMSO+ %

計算結(jié)果：

工作液濃度： mg/ml；

DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；

體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH₂O，混勻澄清。

體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。

注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進(jìn)行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。

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