GDC-0449 (Vismodegib) --- Hedgehog Antagonist

Vismodegib (GDC-0449) is a potent and specific hedgehog pathway inhibitor with an IC50 of 3 nM. It has been approved by FDA to treat BCC, and also in multiple clinical trials to treat advanced solid tumors. It blocks the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. It prevents multiple ATP-binding cassette (ABC) transporters. GDC-0449 also exhibited efficacy in medulloblastoma animal models and primary pancreatic cancer xenograft models. It was shown to inhibit cell growth in cisplatin-resistant lung cancer cells.

Product information

CAS Number: 879085-55-9

Molecular Weight: 421.30

Formula: C19H14Cl2N2O3S

Chemical Name: 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Smiles: CS(=O)(=O)C1=CC(Cl)=C(C=C1)C(=O)NC1=CC(C2=CC=CC=N2)=C(Cl)C=C1

InChiKey: BPQMGSKTAYIVFO-UHFFFAOYSA-N

InChi: InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

GDC-0449 was used at 5-10 µM concentration in the cellular assays.

In Vivo:

GDC-0449 was dosed orally 12.5 mg/kg twice per day (lowest dose), up to 100 mg/kg twice per day (formulated as a suspension in 0.5% methylcellulose, 0.2% Tween-80 (MCT))

References:

1. Robarge KD, et al. GDC-0449-a potent inhibitor of the hedgehog pathway. (2009) Bioorg Med Chem Lett. 19(19):5576-81.
2. Yauch RL, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. (2009) Science 326(5952):572-4.
3. LoRusso PM, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. (2011) Clin Cancer Res.17(8):2502-11
4. Giannetti AM, et al. Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449). (2011) J Med Chem. 54(8):2592-601
5. Lorusso PM, et al. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. (2011) Clin Cancer Res. 17(17):5774-82
6. Philips GM, et al. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.(2011) PLoS One. 6(9):e23943.
7. Metcalfe C, et al. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. (2011) Cancer Res. 71(15):5057-61.
8. Singh BN, et al. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. (2011) PLoS One. 6(11):e27306
9. Tian F, et al. The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. (2012) Anticancer Res. 32(1):89-94

Products are for research use only. Not for human use.

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