RAF265 (CHIR-265)

目錄號(hào)：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(duì)VEGFR2磷酸化表現(xiàn)出有效的抑制作用，無(wú)細(xì)胞試驗(yàn)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(jià)格	庫(kù)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(diǎn)	C-Raf/Raf-1 B-Raf A-raf	點(diǎn)擊展開(kāi)
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(diǎn)擊展開(kāi)
相關(guān)化合物庫(kù)	激酶抑制劑庫(kù) MAPK抑制劑庫(kù) 細(xì)胞周期化合物庫(kù) TGF-beta/Smad信號(hào)通路庫(kù) 抗阿爾茨海默病化合物庫(kù)	點(diǎn)擊展開(kāi)

細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例

細(xì)胞系	實(shí)驗(yàn)類型	給藥濃度	孵育時(shí)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(diǎn)

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(píng)估雙重作用機(jī)制的相對(duì)優(yōu)勢(shì)。^[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(shí)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(shí)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(zhǎng)，比作用于^WTBRAF細(xì)胞選擇性高14倍，比作用于對(duì)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(shuō)明RAF265的細(xì)胞內(nèi)靶點(diǎn)是BRAF。^[4]
激酶實(shí)驗(yàn)	激酶組siRNA合成致死掃描和數(shù)據(jù)分析
激酶實(shí)驗(yàn)	無(wú)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(wú)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(shí)后, 每孔中加入5 mL RAF265，使RAF265 終濃度變?yōu)?.4 mM。RAF265處理72小時(shí)后，通過(guò)CellTiter-Glo(CTG) 檢測(cè)實(shí)驗(yàn)分析細(xì)胞活力，使用Envision獲得實(shí)驗(yàn)數(shù)據(jù)。
細(xì)胞實(shí)驗(yàn)	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(shí)間	72小時(shí)
	方法	5×10⁴A375M 或MV4;11細(xì)胞接種在24孔板中過(guò)夜。更換培養(yǎng)基后, 在孔中加入1.0 μM RAF265, 0.1 μM RAF265, 或無(wú)藥劑(溶劑對(duì)照組)，重復(fù)三次，溫育 4到 5小時(shí)和24到28小時(shí)。加入 1 μCi FDG，溫育2小時(shí)。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(jì)數(shù)器測(cè)定一半樣本放射性。通過(guò)Bradford蛋白檢測(cè)實(shí)驗(yàn)，使用剩余樣本測(cè)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(cè)實(shí)驗(yàn)。溫育72小時(shí)后，清洗細(xì)胞，進(jìn)行CellTiter-Glo檢測(cè)。

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(dòng)物實(shí)驗(yàn)	Animal Models	45只皮下注射3百萬(wàn)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?jī)商焯幚硪淮危掷m(xù)14天。

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試驗(yàn)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(kāi)

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(kāi)

化學(xué)信息&溶解度

分子量	518.41	分子式	C₂₄H₁₆F₆N₆O
CAS號(hào)	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(chǔ)存條件(自收到貨起)	3年-20°C粉狀	儲(chǔ)備液保存和期限建議分裝儲(chǔ)備液，避免反復(fù)凍融！	1年-80°C溶于溶劑
儲(chǔ)存條件(自收到貨起)	3年-20°C粉狀	儲(chǔ)備液保存和期限建議分裝儲(chǔ)備液，避免反復(fù)凍融！	1個(gè)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(huì)降低化合物溶解度，請(qǐng)使用新開(kāi)封DMSO)

Ethanol : 45 mg/mL (86.8 mM)

Water : Insoluble

DMSO : 100 mg/mL ( (192.89 mM) ；DMSO吸濕會(huì)降低化合物溶解度，請(qǐng)使用新開(kāi)封DMSO)

Ethanol : 50 mg/mL (96.44 mM)

Water : Insoluble

摩爾濃度計(jì)算器

體內(nèi)溶解度
批次：

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

動(dòng)物體內(nèi)配方計(jì)算器

實(shí)驗(yàn)計(jì)算

摩爾濃度計(jì)算器

質(zhì)量	濃度	體積	分子量
=	×	×

稀釋計(jì)算器分子量計(jì)算器

動(dòng)物體內(nèi)配方計(jì)算器（澄清溶液）

第一步：請(qǐng)輸入基本實(shí)驗(yàn)信息（考慮到實(shí)驗(yàn)過(guò)程中的損耗，建議多配一只動(dòng)物的藥量）

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

第二步：請(qǐng)輸入動(dòng)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(qǐng)聯(lián)系Selleck為您提供正確的澄清溶液配方）

% DMSO + % + % Tween 80 + % ddH2O

%DMSO+ %

計(jì)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(guò)該批次藥物DMSO溶解度，請(qǐng)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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