受注:045-509-1970 |
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Synonyms | GDC-0449 | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C19H14Cl2N2O3S |
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分子量 | 421.3 | CAS No. | 879085-55-9 | |
Solubility (25°C)* | 体外 | DMSO | 84 mg/mL (199.38 mM) | |
Water | Insoluble | |||
Ethanol | Insoluble | |||
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
製品説明 | Vismodegib (GDC-0449) is a potent, novel and specific hedgehog inhibitor with IC50 of 3 nM and also inhibits P-gp with IC50 of 3.0 μM in a cell-free assay. |
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in vitro | GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. GDC-0449 prevents multiple ATP-binding cassette (ABC) transporters. GDC-0449 also blocks ABCG2, Pgp, and MRP1-important ABC transporters associated with MDR. GDC-0449 is a potent inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, GDC-0449 increases retention of the fluorescent ABCG2 substrate BODIPY and resensitizes these cells. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, GDC-0449 increases the retention of calcein-AM and resensitizes them. GDC-0449 also resensitizes human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to SN-38. The IC50 values of GDC-0449 for prevention of ABCG2 and Pgp are about 1.4 μM and 3.0 μM, respectively. [2] GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in resistant lung cancer cells. [3] |
in vivo | GDC-0449 has been used to treat medulloblastoma in animal models. [2] GDC-0449 prevents the growth of primary pancreatic xenografts without non-specifically inhibiting pancreatic cell proliferation. Oral dosing of GDC-0449 causes tumor regressions in the Ptch(+/-) allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent colorectal cancer models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that GDC-0449 inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μM and 0.267 μM, respectively). Pathway modulation is linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of GDC-0449 is associated with >80% repression of the Hh pathway. [4] |
細胞アッセイ | 細胞株 | MDCKII cells |
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濃度 | 20 μM | |
反応時間 | 2 hours | |
実験の流れ | MDCKII cells are seeded into 24-well plates at a density of 3 × 105 cells per well and are allowed to attach. Medium is then changed to that containing different drugs (50 μM VP, or 20 μM GDC-0449 in DMSO or DMSO alone as control, and nonfluorescent calcein-AM is added to a final concentration of 1.0 μM and incubated at 37 °C for 2 hours. Cells are then washed twice with Ca2+, Mg2+-containing Hank's balanced salt solution buffer and lysed by shaking in 0.01% Triton X-100 in PBS buffer for 1 hour at room temperature or overnight at 4 °C. The lysate is then transferred into 96-well plates, and the fluorescence signal caused by the cell-derived calcein is quantified spectrophotometrically with a SpectraMax M5 Multi-Detection Readerusing an excitation wavelength of 495 nm and an emission wavelength of 515 nm. All manipulations are performed in the dark. All readings are expressed as mean ?SEM normalized to the control. |
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動物実験 | 動物モデル | Ptch(+/-) allograft model, D5123 and 1040830 |
投薬量 | ~ 100 mg/kg | |
投与方法 | Orally |
Data from [Cancer Res, 2014, 72, 5912-20]
Data from [Gut, 2013, 62, 299-309]
Data from [Cancer Res, 2013, 72, 5912-20]
Basal-to-inflammatory transition and tumor resistance via crosstalk with a pro-inflammatory stromal niche [ Nat Commun, 2024, 15(1):8134] | PubMed: 39289380 |
Identification of a distal enhancer regulating hedgehog interacting protein gene in human lung epithelial cells [ EBioMedicine, 2024, 101:105026] | PubMed: 38417378 |
Cellular remodeling and JAK inhibition promote zygotic gene expression in the Ciona germline [ EMBO Rep, 2024, 25(5):2188-2201] | PubMed: 38649664 |
Illuminating Dark Chemical Matter Using the Cell Painting Assay [ J Med Chem, 2024, 10.1021/acs.jmedchem.4c00160] | PubMed: 38687818 |
Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer [ iScience, 2024, 27(6):110027] | PubMed: 38883822 |
Daunorubicin induces GLI1‑dependent apoptosis in colorectal cancer cell lines [ Int J Oncol, 2024, 64(6)66] | PubMed: 38757343 |
Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling [ Nat Metab, 2023, 5(7):1174-1187] | PubMed: 37414930 |
Targetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia [ Nat Commun, 2023, 14(1):7161] | PubMed: 37989729 |
Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer [ Cancer Immunol Res, 2023, 11(5):687-702] | PubMed: 37058110 |
Selective induction of human renal interstitial progenitor-like cell lineages from iPSCs reveals development of mesangial and EPO-producing cells [ Cell Rep, 2023, S2211-1247(23)01614-5] | PubMed: 38237600 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
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