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Vismodegib (GDC-0449)

別名: GDC-0449 中文名稱：維莫德吉

Vismodegib (GDC-0449)是一種新型有效的，特異性hedgehog抑制劑，無(wú)細(xì)胞試驗(yàn)中IC50為3 nM，也會(huì)抑制P-gp，IC50為3.0μM。

Vismodegib (GDC-0449) Chemical Structure

Vismodegib (GDC-0449) Chemical Structure

CAS: 879085-55-9

規(guī)格 價(jià)格 庫(kù)存 購(gòu)買數(shù)量
10mM (1mL in DMSO) 1179.52 現(xiàn)貨
5mg 730.63 現(xiàn)貨
50mg 3046.91 現(xiàn)貨
200mg 7944.3 現(xiàn)貨
1g 16134.3 現(xiàn)貨
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Vismodegib (GDC-0449)相關(guān)產(chǎn)品

相關(guān)信號(hào)通路圖

Hedgehog/Smoothened Signaling Pathways

Hedgehog/Smoothened信號(hào)通路圖

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
Sk-ChA-1? Growth Inhibition Assay 0.25–50 μM 72 h IC50=74.54±2.58μM 25742482
Mz-ChA-1 Growth Inhibition Assay 0.25–50 μM 72 h IC50=54.97±3.45μM 25742482
K562 Function Assay 10 μM 72 h reduces the expression of Gli1? 23319824
T315I BCR-ABL BaF3 Function Assay 10 μM 72 h reduces the expression of Gli1? 23319824
TF-1 BCR-ABL Function Assay 10 μM 72 h reduces the expression of Gli1? 23319824
Shh Light2 Function assay 0.1 uM 36 hrs Inhibition of Smo-mediated Hh signalling pathway in mouse Shh Light2 cells assessed as suppression of Gli1-mRNA expression at 0.1 uM measured after 36 hrs by RT-qPCR analysis. 27736063
SW1353 Antiproliferative assay 10 uM 48 hrs Antiproliferative activity against human SW1353 cells assessed as growth inhibition at 10 uM after 48 hrs by MTT assay. 24491459
DaOY Antiproliferative assay 10 uM 48 hrs Antiproliferative activity against human DaOY cells assessed as growth inhibition at 10 uM after 48 hrs by MTT assay. 24491459
A549 Antiproliferative assay 10 uM 48 hrs Antiproliferative activity against human A549 cells assessed as growth inhibition at 10 uM after 48 hrs by MTT assay. 24491459
HCT116 Antiproliferative assay 10 uM 48 hrs Antiproliferative activity against human HCT116 cells assessed as growth inhibition at 10 uM after 48 hrs by MTT assay. 24491459
NIH3T3-Luc Function assay 1 uM 48 hrs Inhibition of smo-mediated hedgehog signaling pathway in mouse NIH3T3-Luc cells assessed as downregulation of Gli mRNA expression at 1 uM after 48 hrs by real-time PCR analysis. 29499483
NIH/3T3 Function assay 100 nM 36 hrs Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells assessed as downregulation of Shh-induced Gli1 mRNA expression levels at 100 nM after 36 hrs by RT-qPCR analysis. 28873303
C3H10T1/2 Function assay 100 nM 36 hrs Inhibition of hedgehog signaling pathway in mouse C3H10T1/2 cells assessed as downregulation of Shh-induced Gli1 mRNA expression levels at 100 nM after 36 hrs by RT-qPCR analysis. 28873303
NIH/3T3 Function assay 100 nM 36 hrs Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells assessed as downregulation of Shh-induced ptch1 mRNA expression levels at 100 nM after 36 hrs by RT-qPCR analysis. 28873303
C3H10T1/2 Function assay 100 nM 36 hrs Inhibition of hedgehog signaling pathway in mouse C3H10T1/2 cells assessed as downregulation of Shh-induced ptch1 mRNA expression levels at 100 nM after 36 hrs by RT-qPCR analysis. 28873303
medulloblastoma cell Antiproliferative assay up to 30 uM 72 hrs Antiproliferative activity against mouse Ptch+/- p53-/- medulloblastoma cells assessed as reduction in cell proliferation up to 30 uM after 72 hrs by MTS assay. 28873303
NIH/3T3 Function assay 10 uM Inhibition of Hedgehog signaling in mouse NIH/3T3 cells assessed as down regulation of mPTCH1 mRNA expression at 10 uM. 24491459
MSC Function assay 20 to 80 uM Inhibition of hedgehog signaling in mouse MSC cells assessed as down regulation of alkaline phosphatase at 20 to 80 uM. 24491459
C3H10T1/2 Function assay 4.1 to 1000 nM Allosteric inhibition of Smo in mouse C3H10T1/2 cells assessed as inhibition of purmorphamine-induced Gli1 transcriptional activity at 4.1 to 1000 nM by qPCr analysis. 23074541
C3H10T1/2 Function assay 4.1 to 1000 nM Competitive inhibition of Smo in mouse C3H10T1/2 cells assessed as inhibition of SAG-induced Gli1 transcriptional activity at 4.1 to 1000 nM by qPCR analysis. 23074541
Shh-Light 2 Function assay 2 days Antagonist activity at Smo in mouse Shh-Light 2 cells assessed as inhibition of Shh-induced Gli1-reporter activity after 2 days by dual-luciferase reporter gene method, IC50 = 0.0015 μM. 23063522
Light2 Function assay 48 hrs Inhibition of hedgehog signaling pathway in mouse Light2 cells after 48 hrs by Gli-luciferase reporter gene assay, IC50 = 0.00246 μM. 29739714
C3H10T1/2 Function assay 20 hrs Inhibition of Smo in mouse C3H10T1/2 cells using human recombinant SHH assessed as effect on SMO/SHH transient transcriptional activation after 20 hrs by Gli-luciferase reporter assay, IC50 = 0.005 μM. 24900436
NIH/3T3 Function assay 24 hrs Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells measured after 24 hrs by Gli-dual luciferase reporter gene assay, IC50 = 0.005 μM. 27810591
NIH3T3 Function assay 48 hrs Inhibition of smo-mediated hedgehog signaling pathway in mouse NIH3T3 cells expressing GRE-Luc reporter gene assessed as inhibition of SAG-induced GRE-Luc reporter activity after 48 hrs by luminescence assay, IC50 = 0.006 μM. 29499483
HEK293 Function assay 2 hrs Displacement of BODIPY-labelled cyclopamine from human Smo receptor expressed in HEK293 cells after 2 hrs by fluorescence microscopy, IC50 = 0.007 μM. 22268551
NIH/3T3 Function assay 48 hrs Inhibition of Hedgehog signaling pathway in mouse NIH/3T3 cells assessed as reduction in Sonic hedgehog-induced Gli luciferase activity after 48 hrs by Dual-luciferase reporter gene assay, IC50 = 0.00717 μM. 30249494
NIH3T3 Function assay 48 hrs Inhibition of hedgehog signalling in mouse NIH3T3 cells stably transfected with Gli-luciferase construct incubated for 48 hrs by dual luciferase reporter gene assay, IC50 = 0.0072 μM. 26827136
NIH3T3 Function assay 48 hrs Inhibition of Sonic-induced hedgehog signalling in mouse NIH3T3 cells after 48 hrs by Gli-luciferase reporter assay, IC50 = 0.0072 μM. 26820554
NIH3T3 Function assay 48 hrs Inhibition of SHH signaling pathway in mouse NIH3T3 cells measured after 48 hrs by Gli-luciferase reporter assay, IC50 = 0.0072 μM. 24176396
NIH/3T3 Function assay 48 hrs Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells after 48 hrs by Gli-luciferase reporter gene assay, IC50 = 0.0072 μM. 24486203
C3H10T1/2 Function assay 6 hrs Inhibition of SAG-induced differentiation of mouse mesenchymal pluripotent C3H10T1/2 cells to alkaline phosphatase positive oeseoblasts after 6 hrs, IC50 = 0.011 μM. 22268551
TM3 Function assay 48 hrs Inhibition of Hh signaling pathway in mouse TM3 cells assessed as downregulation of Gli1 gene expression after 48 hrs by luciferase reporter gene assay, EC50 = 0.013 μM. 26976215
S12 Function assay 48 hrs Inhibition of human SHH pathway in mouse S12 cells assessed as GLI-mediated transcriptional activity after 48 hrs by luciferase reporter gene assay, IC50 = 0.015 μM. 21438527
U2OS Function assay 2 hrs Displacement of [3H]cyclopamine from wild type Smo expressed in U2OS cells after 2 hrs by scintillation counting, Ki = 0.0162 μM. 23063522
NIH3T3 Function assay 30 hrs Inhibition of Smo receptor (unknown origin) expressed in NIH3T3 cells assessed as inhibition of Smo agonist SAG-induced GRE activation after 30 hrs by luciferase reporter gene assay, IC50 = 0.023 μM. 24726807
medulloblastoma cell Antiproliferative assay 36 hrs Antiproliferative activity against Ptch+/- and p53-/- mouse medulloblastoma cells after 36 hrs by Brdu incorporation assay, IC50 = 0.0304 μM. 28688278
ASZ001 Function assay 48 hrs Inhibition of Hedgehog signaling in mouse ASZ001 cells assessed as downregulation of Gli1 mRNA expression after 48 hrs by RT-PCR analysis, IC50 = 0.04 μM. 24900716
NIH/3T3 Function assay 48 hrs Antagonist activity at Smo receptor in mouse NIH/3T3 cells harboring GRE-Luc assessed as inhibition of SAG-induced Hh signaling pathway preincubated with cells followed by SAG addition measured after 48 hrs by luciferase reporter gene assay, IC50 = 0.046 μM. 29857275
Light2 Function assay 30 hrs Inhibition of hedgehog signaling pathway in mouse Light2 cells in Shh conditioned medium after 30 hrs by Gli-Renilla luciferase reporter gene assay, IC50 = 0.05 μM. 30099257
C3H10T1/2 Function assay 6 days Inhibition of hedgehog signaling pathway-mediated differentiation of mouse C3H10T1/2 cells assessed as decrease in SAG-induced ALP activity after 6 days by chemiluminescence-based assay, IC50 = 0.05 μM. 30099257
DaOY Function assay 48 hrs Inhibition of Hedgehog signaling in human DaOY cells assessed as downregulation of Gli1 mRNA expression after 48 hrs by RT-PCR analysis, IC50 = 0.086 μM. 24900716
C3H10T1/2 Function assay 1 hr Inhibition of Hedgehog signaling pathway in mouse C3H10T1/2 cells assessed as reduction in purmorphamine-induced increase in alkaline phosphatase level using CDP-star as substrate pretreated for 1 hr followed by purmorphamine addition measured after 5 day, IC50 = 0.14 μM. 28947939
M210B4 Function assay 24 hrs Inhibition of Hedgehog signaling in mouse M210B4 cells assessed as downregulation of Ptch mRNA expression after 24 hrs by RT-PCR analysis, IC50 = 0.14 μM. 24900716
M210B4 Function assay 24 hrs Inhibition of Hedgehog signaling in mouse M210B4 cells assessed as downregulation of Gli1 mRNA expression after 24 hrs by RT-PCR analysis, IC50 = 0.2 μM. 24900716
Shh Light2 Function assay 1 hr Inhibition of Hedgehog signaling in mouse Shh Light2 cells assessed as reduction in purmorphamine-induced Gli mediated transcriptional activity pretreated for 1 hr followed by purmorphamine addition measured after 48 hrs by luciferase reporter gene assay, IC50 = 0.98 μM. 28947939
S12 Function assay 48 hrs Inhibition of human SHH pathway in mouse S12 cells assessed as GLI-mediated transcriptional activity after 48 hrs by luciferase reporter gene assay in presence of 0.5 mg/mL human alpha-1-acid glycoprotein, IC50 = 1.75 μM. 21438527
Calu6 Function assay 4 hrs Plasma concentration in human Calu6 cells xenografted in nude mouse at 75 mg/kg, po bid measured after 4 hrs post fifth dose, Cp = 23 μM. 19716296
T47D Cytotoxicity assay 72 hrs Cytotoxicity against human T47D cells after 72 hrs by MTT assay, IC50 = 41.34 μM. 29107429
LS180 Antiproliferative assay 72 hrs Antiproliferative activity against human LS180 cells after 72 hrs by sulforhodamine-B assay, IC50 = 45 μM. 30099257
LS174T Antiproliferative assay 72 hrs Antiproliferative activity against human LS174T cells after 72 hrs by CellTiter-Glo luminescent cell viability assay, IC50 = 45.81 μM. 26820554
BxPC3 Antiproliferative assay 72 hrs Antiproliferative activity against human BxPC3 cells after 72 hrs by CellTiter-Glo luminescent cell viability assay, IC50 = 47.95 μM. 26820554
S12 Function assay 48 hrs Inhibition of human SHH pathway in mouse S12 cells assessed as GLI-mediated transcriptional activity after 48 hrs by luciferase reporter gene assay in presence of 1 mg/mL human alpha-1-acid glycoprotein. 21438527
C3H10T1/2 Function assay 24 hrs Inhibition of hedgehog signaling pathway-mediated GLI1 mRNA expression in mouse C3H10T1/2 cells after 24 hrs by RT-PCR analysis in presence of (1R,3aR,4S,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-yl 3-hydroxybenzoate. 24730984
C3H10T1/2 Function assay 24 hrs Inhibition of hedgehog signaling pathway-mediated GLI1 mRNA expression in mouse C3H10T1/2 cells after 24 hrs by RT-PCR analysis in presence of VD3. 24730984
EW-11 Growth Inhibition Assay IC50=22.8022 μM SANGER
COLO-829 Growth Inhibition Assay IC50=22.1871 μM SANGER
LB2241-RCC Growth Inhibition Assay IC50=21.8441 μM SANGER
C2BBe1 Growth Inhibition Assay IC50=21.1058 μM SANGER
GCT Growth Inhibition Assay IC50=20.8824 μM SANGER
NCI-SNU-1 Growth Inhibition Assay IC50=20.0196 μM SANGER
NCI-H82 Growth Inhibition Assay IC50=19.8386 μM SANGER
DU-145 Growth Inhibition Assay IC50=18.32 μM SANGER
MDA-MB-361 Growth Inhibition Assay IC50=17.2711 μM SANGER
DMS-273 Growth Inhibition Assay IC50=16.6713 μM SANGER
NB7 Growth Inhibition Assay IC50=15.891 μM SANGER
HOS Growth Inhibition Assay IC50=15.6719 μM SANGER
NY Growth Inhibition Assay IC50=14.8903 μM SANGER
D-423MG Growth Inhibition Assay IC50=12.7657 μM SANGER
MC-IXC Growth Inhibition Assay IC50=12.2292 μM SANGER
KYSE-150 Growth Inhibition Assay IC50=11.5841 μM SANGER
BHT-101 Growth Inhibition Assay IC50=11.38 μM SANGER
HuO-3N1 Growth Inhibition Assay IC50=9.60108 μM SANGER
ACN Growth Inhibition Assay IC50=8.50109 μM SANGER
HDLM-2 Growth Inhibition Assay IC50=8.04766 μM SANGER
23132-87 Growth Inhibition Assay IC50=4.40147 μM SANGER
D-542MG Growth Inhibition Assay IC50=1.86737 μM SANGER
HCE-T Growth Inhibition Assay IC50=1.32247 μM SANGER
IGROV-1 Growth Inhibition Assay IC50=0.07248 μM SANGER
NCI-H526 Growth Inhibition Assay IC50=23.4717 μM SANGER
SF295 Growth Inhibition Assay IC50=24.0252 μM SANGER
D-566MG Growth Inhibition Assay IC50=25.2943 μM SANGER
8505C Growth Inhibition Assay IC50=25.6331 μM SANGER
HT-29 Growth Inhibition Assay IC50=26.0431 μM SANGER
NBsusSR Growth Inhibition Assay IC50=26.8006 μM SANGER
BV-173 Growth Inhibition Assay IC50=28.3182 μM SANGER
CTB-1 Growth Inhibition Assay IC50=30.1031 μM SANGER
JAR Growth Inhibition Assay IC50=32.5371 μM SANGER
CAMA-1 Growth Inhibition Assay IC50=33.4615 μM SANGER
CAL-51 Growth Inhibition Assay IC50=34.7176 μM SANGER
A172 Growth Inhibition Assay IC50=37.4921 μM SANGER
QIMR-WIL Growth Inhibition Assay IC50=38.0708 μM SANGER
AsPC-1 Growth Inhibition Assay IC50=38.4651 μM SANGER
MKN7 Growth Inhibition Assay IC50=39.0079 μM SANGER
ONS-76 Growth Inhibition Assay IC50=43.3057 μM SANGER
RS4-11 Growth Inhibition Assay IC50=44.0752 μM SANGER
NOS-1 Growth Inhibition Assay IC50=44.6031 μM SANGER
A101D Growth Inhibition Assay IC50=44.8023 μM SANGER
HCC1806 Growth Inhibition Assay IC50=46.1148 μM SANGER
CAL-27 Growth Inhibition Assay IC50=47.7246 μM SANGER
BT-549 Growth Inhibition Assay IC50=48.5315 μM SANGER
LCLC-97TM1 Growth Inhibition Assay IC50=49.2413 μM SANGER
A4-Fuk Growth Inhibition Assay IC50=49.849 μM SANGER
OVCAR-4 Growth Inhibition Assay IC50=50.0601 μM SANGER
HD-MY-Z Growth Inhibition Assay IC50=50.7764 μM SANGER
NCI-H292 Growth Inhibition Assay IC50=50.8758 μM SANGER
Smo-WT Growth Inhibition Assay IC50?of 14?nM 24291104
Smo-D473H? Growth Inhibition Assay IC50?of 7.1?μM 24291104
NIH/3T3 Function assay Inhibition of hedgehog signaling (unknown origin) expressed in mouse NIH/3T3 cells by Gli-dual-luciferase reporter assay, IC50 = 0.0023 μM. 27180012
NIH/3T3 Light2 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 Light2 cells by Gli-luciferase reporter gene assay, IC50 = 0.0023 μM. 28688278
HEPM Function assay Inhibition of SHH in human HEPM cells by Gli-luciferase reporter gene assay, INH = 0.0028 μM. 19716296
Shh Light2 Function assay Inhibition of SHH in mouse Shh Light2 cells by GLI-responsive firefly luciferase reporter gene assay, IC50 = 0.003 μM. 19309080
HEPM Function assay Inhibition of Hedgehog signaling in human HEPM cells assessed as reduction in receptor-mediated Gli1 mRNA expression by reporter gene assay, INH = 0.003 μM. 20875741
Shh-light2 Function assay Inhibition of Smo-mediated Hh signaling in human Shh-light2 cells by luciferase reporter gene assay, IC50 = 0.007 μM. 22268551
NIH3T3 Function assay Inhibition of hedgehog receptor signaling pathway in mouse NIH3T3 cells transfected with Gli-reporter gene by luciferase reporter gene assay, IC50 = 0.00717 μM. 24923765
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells by Gli1-luciferase reporter gene assay, IC50 = 0.0072 μM. 24405704
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells carrying stably transfected Gli-reporter construct by luciferase reporter assay, IC50 = 0.0072 μM. 28642101
HCC827 Function assay Displacement of [3H]-cyclopamine from SMO V404M mutant in gefitinib resistant human HCC827 cells by scintillation counting, Ki = 0.0122 μM. 28787156
C3H10T1/2 Function assay Inhibition of SHH in mouse C3H10T1/2 cells by Gli-luciferase reporter gene assay, IC50 = 0.013 μM. 19716296
S12 Function assay Inhibition of Hedgehog signaling in mouse S12 cells assessed as reduction in receptor-mediated Gli1 mRNA expression by reporter gene assay, INH = 0.013 μM. 20875741
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells expressing wild type Smo assessed as reduction in Gli mRNA expression by RT-PCR method, IC50 = 0.0144 μM. 27810591
NIH/3T3 Function assay Inhibition of SMO in mouse NIH/3T3 cells assessed as inhibition of SAG-induced hedgehog-mediated luminescence signaling by GRE-luciferase reporter gene assay, IC50 = 0.016 μM. 26119500
Shh Light2 Function assay Antagonist activity at smoothened (unknown origin) expressed in mouse Shh Light2 cells co-expressing Gli-dependent reporter gene assessed as inhibition of Hh signaling by dual luciferase reporter gene assay, IC50 = 0.033 μM. 24491459
Light2 Function assay Inhibition of hedgehog signaling pathway in mouse Light2 cells in Shh conditioned medium by Gli-luciferase reporter gene assay, IC50 = 0.039 μM. 28873303
Shh Light2 Function assay Inhibition of Smo-mediated Hh signalling pathway in mouse Shh Light2 cells by Gli-luciferase reporter gene assay, IC50 = 0.0392 μM. 27736063
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells harboring Smo D477H mutant assessed as reduction in Gli mRNA expression by RT-PCR method, IC50 = 1.196 μM. 27810591
Calu-6 Function assay Plasma concentration in Calu-6 cells xenografted nude mouse PK/PD model at 75 mg/kg, po bid for 5 days measured 4 hrs post last dose relative to untreated control, Cp = 23 μM. 20875741
medulloblastoma cell Antitumor assay Antitumor activity against mouse medulloblastoma cells xenografted in Ptch +/- mouse assessed as decrease in tumor volume at 12.5 mg/kg, po bid. 19716296
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
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells. 29435139
medulloblastoma cell Apoptosis assay Induction of apoptosis in mouse Ptch+/- p53-/- medulloblastoma cells implanted in athymic nude mouse at 12.5 mg/kg, ip bid for 15 consecutive days by TUNEL assay. 28873303
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway expressed in mouse NIH/3T3 cells assessed as inhibition of hedgehog-induced Gli-2 accumulation at tip of primary cilia by DAPI staining based confocal microscopic analysis. 27810591
NIH/3T3 Function assay Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells assessed as inhibition of hedgehog-induced Smo-EGFP ciliary translocation by DAPI staining based confocal microscopic analysis. 27810591
medulloblastoma cell Anti-tumor assay Anti-tumor activity against mouse Ptch+/- p53-/- medulloblastoma cells implanted in athymic nude mouse assessed as tumor growth inhibition at 20 mg/kg, po administered twice daily via gavage measured every other day during compound dosing. 29739714
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生物活性

產(chǎn)品描述 Vismodegib (GDC-0449)是一種新型有效的，特異性hedgehog抑制劑，無(wú)細(xì)胞試驗(yàn)中IC50為3 nM，也會(huì)抑制P-gp，IC50為3.0μM。
靶點(diǎn)
Hedgehog [1]
(Cell-free assay)
3 nM
體外研究(In Vitro)
體外研究活性

GDC-0449有效抑制hedgehog通路，是一種新型及特定合成的小分子抑制劑，IC50為3nM。[1] GDC-0449作用于Hedgehog信號(hào)通路，阻斷Hedgehog配位體，即細(xì)胞表面受體PTCH 及SMO的活性，從而阻斷Hedgehog信號(hào)通路。在組織生長(zhǎng)和修復(fù)方面，Hedgehog信號(hào)通路意義重大。Hedgehog通路信號(hào)的異常激活，及不受控制的細(xì)胞增殖，可能與Hedgehog配位體，即細(xì)胞表面受體PTCH 及SMO的突變有關(guān)。在體外，GDC-0449在不抑制胰臟細(xì)胞增殖的前提下阻止原代胰臟移植物的生長(zhǎng)，這項(xiàng)結(jié)果最近已經(jīng)應(yīng)用到臨床。GDC-0449也抑制ABCG2, P-糖蛋白, 及和MDR有關(guān)聯(lián)的重要MRP1 ABC載體。GDC-0449也阻斷其他多種ABC載體。ABC載體屬于一個(gè)膜蛋白家族，它的過(guò)量表達(dá)和耐藥性有關(guān)，這也是治療癌癥的一個(gè)重大障礙。GDC-0449強(qiáng)抑制兩種ABC載體，ABCG2/BCRP和ABCB1/P-糖蛋白，也溫和抑制ABCC1/MRP1。在ABCG2過(guò)量表達(dá)的HEK293細(xì)胞中, GDC-0449可以提高熒光ABCG2底物BODIPY-哌唑嗪的保持力，也可用米托蒽醌再次處理這些細(xì)胞，產(chǎn)生抗腫瘤的ABCG2底物。實(shí)驗(yàn)使Madin-Darby犬的腎臟細(xì)胞中過(guò)量表達(dá)P糖蛋白或者M(jìn)RP1，GDC-0449 提高了鈣黃綠素-AM的保持力，然后載用秋水仙素處理這些細(xì)胞。另外，用米托蒽醌,托泊替康,SN-38處理的過(guò)量表達(dá)ABCG2的人類非小細(xì)胞肺癌細(xì)胞NCI-H460/par和NCI-H460/MX20，用GDC-0449再次處理。GDC-0449 作用于ABCG2 和 Pgp 的IC50值分別為1.4μM和 3.0 μM。[2]GDC-0449 改變細(xì)胞內(nèi)Ca2+ 平衡，且作用于肺癌細(xì)胞， 抑制細(xì)胞生長(zhǎng)。[3]
細(xì)胞實(shí)驗(yàn) 細(xì)胞系 MDCKII細(xì)胞
濃度 20 μM
孵育時(shí)間 2小時(shí)
方法

MDCKII細(xì)胞按每孔3x105密度接種在24孔板中。培養(yǎng)液包含不同藥物，實(shí)驗(yàn)組為50 µM VP,50 µM吲哚美辛,或者20 µM GDC-0449溶解在DMSO中，對(duì)照組只含有DMSO。然后加入非熒光的鈣黃綠素-AM，最終濃度達(dá)到1.0 µM。然后在37oC溫育2小時(shí)。細(xì)胞用含Ca2+,Mg2+的Hank's平衡鹽溶液buffer沖洗2次，然后震蕩1小時(shí)溶解在含0.01% Triton X-100的磷酸緩沖液中，然后放在4oC下過(guò)夜。溶解的物質(zhì)然后轉(zhuǎn)移到96孔板上，鈣黃綠素引起的熒光信號(hào)用分光光度法定量。所有的實(shí)驗(yàn)操作需在暗中進(jìn)行，所有的讀數(shù)用平均值±SEM表示。
實(shí)驗(yàn)圖片 檢測(cè)方法 檢測(cè)指標(biāo) 實(shí)驗(yàn)圖片 PMID
Western blot Fas / DR4 / DR5 / Cleaved PARP / Bcl-2 / Cleaved caspase-3 / PDGFRα p-GSK3β / GSK3β / p-Akt / Akt / Gli1 Gli1 / SOX2 / OCT4 p53 / Cyclin D1 / p21 Bcl-2 / Bax 22087285
Immunofluorescence Gli1 / Gli2 22087285
Growth inhibition assay Cell viability 29042665
體內(nèi)研究(In Vivo)
體內(nèi)研究活性

GDC-0449已經(jīng)用于治療動(dòng)物模型的成髓細(xì)胞瘤。[2] GDC-0449 抑制原代胰腺移植瘤生長(zhǎng)，但是不抑制細(xì)胞增殖。GDC-0449按25 mg/kg 以上劑量口服給藥髓母細(xì)胞瘤Ptch(+/-)異體移植物模型，引起細(xì)胞衰退，按92 mg/kg劑量處理兩種配位體依賴的結(jié)腸直腸癌模型D5123和1040830，每天處理兩次，抑制腫瘤生長(zhǎng)。分析Hh通路活性和 PK/PD 模型顯示GDC-0449抑制 Gli1，IC50值與GDC-0449作用于髓母細(xì)胞瘤和D5123模型的IC50值差不多(分別為0.165 μM ±11.5% 和0.267 μM ±4.83%)。[4]
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06344052 Recruiting
Basal Cell Carcinoma
Stamford Pharmaceuticals Inc.
 April 9 2024 Phase 2
NCT03610022 Completed
Metastatic Basal Cell Carcinoma|Locally Advanced Basal Cell Carcinoma
University Hospital Bordeaux
 September 3 2018 Phase 4
NCT03035188 Completed
Basal Cell Carcinoma
SRH Wald-Klinikum Gera GmbH
 January 2017 Phase 2
NCT02781389 Completed
Basal Cell Carcinoma
University Hospital Essen|OnkoDataMed GmbH
 April 29 2016 --
NCT02593760 Completed
Myelofibrosis
Hoffmann-La Roche
 January 25 2016 Phase 1
NCT02648048 Completed
Idiopathic Pulmonary Fibrosis
Hoffmann-La Roche
 January 15 2016 Phase 1

化學(xué)信息&溶解度

分子量 421.3 分子式

C19H14Cl2N2O3S
CAS號(hào) 879085-55-9 SDF Download Vismodegib (GDC-0449) SDF
Smiles CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
儲(chǔ)存條件(自收到貨起)

體外溶解度
批次：

DMSO : 84 mg/mL ( (199.38 mM) ；DMSO吸濕會(huì)降低化合物溶解度，請(qǐng)使用新開封DMSO)

Water : Insoluble

Ethanol : 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

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）

mg/kg g μL 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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