Vismodegib (GDC-0449)

Catalog No.S1082 Batch:S108214

Technical Data

Formula	C₁₉H₁₄Cl₂N₂O₃S
Molecular Weight	421.3	CAS No.	879085-55-9
Solubility (25°C)*	In vitro	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. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description

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.

Targets

Hedgehog ^[1]
(Cell-free assay)

3 nM

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-prazosin and resensitizes these cells to mitoxantrone. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, GDC-0449 increases the retention of calcein-AM and resensitizes them to colchicine. GDC-0449 also resensitizes human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or 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 cisplatin-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]

Protocol (from reference)

Cell Assay:^{^[2]}	Cell lines MDCKII cells Concentrations 20 μM Incubation Time 2 hours Method 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, 50 μM indomethacin, 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.
Animal Study:^{^[4]}	Animal Models Ptch(+/-) allograft model, D5123 and 1040830 Dosages ~ 100 mg/kg Administration Orally

Cell Assay:^{^[2]}

Cell lines
MDCKII cells
Concentrations
20 μM
Incubation Time
2 hours
Method
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, 50 μM indomethacin, 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.

Animal Study:^{^[4]}

Animal Models
Ptch(+/-) allograft model, D5123 and 1040830
Dosages
~ 100 mg/kg
Administration
Orally

References

[4] Wong H, et al. Clin Cancer Res. 2011, 17(14), 4682-4692.

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Customer Product Validation

: Data from [Cancer Res, 2014, 72, 5912-20]

: Data from [Gut, 2013, 62, 299-309]

: Data from [Cancer Res, 2013, 72, 5912-20]

: Data from [Data independently produced by PLoS One, 2013, 8, e74141]

Selleck's Vismodegib (GDC-0449) has been cited by 209 publications

Identification of a distal enhancer regulating hedgehog interacting protein gene in human lung epithelial cells [ EBioMedicine, 2024, 101:105026]	PubMed: 38417378
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
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
The HEDGEHOG-GLI1 pathway is important for fibroproliferative properties in keloids and as a candidate therapeutic target [ Commun Biol, 2023, 6(1):1235]	PubMed: 38062202
Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells [ Int J Mol Sci, 2023, 24(13)10448]	PubMed: 37445628
IFN-γ promotes radioresistant Nestin-expressing progenitor regeneration in the developing cerebellum by augmenting Shh ligand production [ CNS Neurosci Ther, 2023, 10.1111/cns.14485]	PubMed: 37789668
Triptolide inhibits epithelial ovarian tumor growth by blocking the hedgehog/Gli pathway [ Aging (Albany NY), 2023, 10.18632/aging.205110]	PubMed: 37851362
Signaling Switching from Hedgehog-GLI to MAPK Signaling Potentially Serves as a Compensatory Mechanism in Melanoma Cell Lines Resistant to GANT-61 [ Biomedicines, 2023, 11(5)1353]	PubMed: 37239024
The Chordate Origins of Heart Regeneration [ bioRxiv, 2023, 10.1101/2023.09.19.558507]	PubMed: 37781597

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