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別名: DP-4978
LY03009120 (DP-4978)是一種有效的泛Raf抑制劑,在A375細胞中對A-raf,B-Raf,和 C-Raf的IC50分別為44 nM,31-47 nM,和 42 nM。LY03009120 可誘導(dǎo)自噬。Phase 1。
LY3009120 Chemical Structure
CAS: 1454682-72-4
細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
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HCT116 | Function assay | <100 nM | Paradoxical activation of RAS/RAF/MEK signaling pathway in human HCT116 cells expressing wild type BRAF assessed as ERK phosphorylation at <100 nM | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to CRAF in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.042μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to ZAK in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.039μM. | 25965804 | |
A375 | Function assay | 72 hrs | Inhibition of BRAF V600E mutant in human A375 cells assessed as inhibition of ERK phosphorylation measured after 72 hrs by ELISA assay, IC50=0.037μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to BRAF in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.031μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to EphA2 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.02μM. | 25965804 | |
A375 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human A375 cells after 72 hrs by resazurin assay, IC50=0.0092μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to ARAF in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.044μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to p38 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.061μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to FYN in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.091μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to MAP3K1 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.098μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to EphB4 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.1μM. | 25965804 | |
HCT116 | Antiproliferative assay | 67 hrs | Antiproliferative activity against human HCT116 cells after 67 hrs by resazurin assay, IC50=0.22μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to CSK in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.29μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to SRC in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.31μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to ABL in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.38μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to IRAK1 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.39μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to GCN2 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.45μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to JNK in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.47μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to MAP2K5 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.8μM. | 25965804 | |
A375 | Function assay | 15 mins | Competitive binding affinity to KHS1 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.97μM. | 25965804 | |
MV4-11 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MV4-11 cells after 72 hrs by Cell-Titer Glo assay, IC50=0.1μM. | 30529543 | |
SK-MEL-2 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SK-MEL-2 cells after 72 hrs by Cell-Titer Glo assay, IC50=0.2μM. | 30529543 | |
A375 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human A375 cells after 72 hrs by Cell-Titer Glo assay, IC50=0.3μM. | 30529543 | |
SW579 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SW579 cells after 72 hrs by Cell-Titer Glo assay, IC50=0.9μM. | 30529543 | |
HT-29 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human HT-29 cells after 72 hrs by Cell-Titer Glo assay, IC50=0.9μM. | 30529543 | |
HepG2 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human HepG2 cells after 72 hrs by Cell-Titer Glo assay, IC50=2.6μM. | 30529543 | |
HCT116 | Function assay | Inhibition of KRAS G13D mutant in human HCT116 cells assessed as inhibition of ERK phosphorylation by ELISA, IC50=0.15μM. | 25965804 | ||
A375 | Function assay | In vivo inhibition of BRAF V600E mutant in human A375 cells xenografted in po dosed NIH nude rat assessed as plasma concentration required to inhibit ERK phosphorylation by 50%, INH=0.165μM. | 25965804 | ||
A375 | Function assay | Inhibition of desthiobiotin-ATP acylphosphate probe binding to B-Raf in human A375 cells by MS analysis, IC50=0.031μM. | 30529543 | ||
A375 | Function assay | Inhibition of desthiobiotin-ATP acylphosphate probe binding to C-Raf in human A375 cells by MS analysis, IC50=0.042μM. | 30529543 | ||
A375 | Function assay | Inhibition of desthiobiotin-ATP acylphosphate probe binding to A-Raf in human A375 cells by MS analysis, IC50=0.044μM. | 30529543 | ||
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產(chǎn)品描述 | LY03009120 (DP-4978)是一種有效的泛Raf抑制劑,在A375細胞中對A-raf,B-Raf,和 C-Raf的IC50分別為44 nM,31-47 nM,和 42 nM。LY03009120 可誘導(dǎo)自噬。Phase 1。 | ||||||
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靶點 |
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體外研究(In Vitro) | ||||
體外研究活性 | LY3009120抑制A375和 HCT116細胞的生長,IC50分別為9.2和220 μM。LY3009120抑制酪氨酸激酶KDR,IC50為3.9 μM。[1] | |||
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激酶實驗 | 使用KiNativ試驗測定激酶活性 | |||
化合物在A375細胞裂解物中使用基于ATP的探針在5 μM下篩選。IC50值以微摩爾單位表示。細胞沉淀重懸浮在4體積裂解緩沖液[25 mM Tris pH 7.6,150 mM NaCl,1% CHAPS,1% Tergitol NP-40 型,1% v/v 磷酸酶抑制劑混合物II]中,使用尖端超聲波儀聲處理,并均質(zhì)化。裂解產(chǎn)物通過100,000 g下離心分離30分鐘除去。澄清的裂解液通過0.22 μM注射過濾器和凝膠過濾到反應(yīng)緩沖液[20 mM Hepes pH 7.8,150 mM NaCl,0.1% triton X-100,1% v/v 磷酸酶抑制劑混合物II]。抑制劑處理和探針標記之前,將終濃度為20 mM 的MnCl2加入裂解液。用于IC50測定的終抑制劑濃度為10,1,0.1,和 0.01 μM。ATP競爭性實驗在1,000,100,10,和1 μM ATP下進行。所有抑制劑的處理在室溫下進行。 | ||||
細胞實驗 | 細胞系 | A375 和 HCT116 細胞 | ||
濃度 | 0.51 μM | |||
孵育時間 | 67 h | |||
方法 | 簡而言之,細胞在DMEM高濃度葡萄糖中生長,用10%胎牛血清和1%青霉素/鏈霉素/L-谷氨酰胺增補,在37℃,5% CO2,和95%濕度下培育。允許細胞擴增到70-95%的融合度。連續(xù)稀釋的測試化合物分配加入到384孔黑色透明底板。每孔加入包含625個細胞的50 μL完全生長培養(yǎng)基。板在37℃,5% CO2,和95%濕度下培育67小時。然后,10 μL包含440 μM 刃天青的PBS溶液加入板的每孔中,板在37℃,5% CO2,和95%濕度下再培育5小時。板在Synergy2閱讀器上使用540 nm激發(fā)波長和600 nm發(fā)射波長讀取。得到的數(shù)據(jù)使用Prism軟件分析以計算IC 50值。 | |||
實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | PMID |
Western blot | Beclin-1 / Mcl-1 / LC3 / p62 p-EGFR / EGFR / p-BRAF / BRAF / p-CRAF / CRAF / p-MEK / MEK / p-AKT / AKT | 28382170 |
體內(nèi)研究(In Vivo) | ||
體內(nèi)研究活性 | 在負荷BRAF V600E ST019VR PDX腫瘤的大鼠體內(nèi),LY3009120 (15 or 30 mg/kg, p.o.)劑量依賴性抑制腫瘤生長。在負荷A375異種移植物的裸鼠體內(nèi),LY3009120 (3到50 mg/kg, p.o.)單劑量口服治療劑量依賴性抑制磷酸-ERK,4.36 mg/kg劑量下抑制50%磷酸- ERK (EC50),68.9 ng/mL或165 nM血漿濃度下達到50%磷酸- ERK (EC50) 抑制率。[1] | |
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動物實驗 | Animal Models | 負荷BRAF V600E ST019VR PDX腫瘤的雌性 NIH裸鼠 |
Dosages | 30 mg/kg | |
Administration | p.o. |
NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
---|---|---|---|---|---|
NCT02014116 | Terminated | Neoplasms|Neoplasm Metastasis|Melanoma|Carcinoma Non-Small-Cell Lung|Colorectal Neoplasms |
Eli Lilly and Company |
November 26 2013 | Phase 1 |
分子量 | 424.51 | 分子式 | C23H29FN6O |
CAS號 | 1454682-72-4 | SDF | Download LY3009120 SDF |
Smiles | CC1=CC(=C(C=C1C2=C(N=C3C(=C2)C=NC(=N3)NC)C)NC(=O)NCCC(C)(C)C)F | ||
儲存條件(自收到貨起) | |||
體外溶解度 |
DMSO : 20 mg/mL ( (47.11 mM) ;DMSO吸濕會降低化合物溶解度,請使用新開封DMSO) Water : Insoluble Ethanol : Insoluble |
摩爾濃度計算器 |
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)
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)
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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問題 1:
I am trying to figure out solubility of the drug LY3009120 Catalog #7842 for in vivo studies. I need some details on the formulation and how it is made to dissolve the chemical?
回答:
It can dissolve in 4% DMSO/30% PEG 300/5% Tween 80/ddH2O at 1 mg/ml clearly, and in 0.5% CMC Na at 30 mg/ml as a suspension.