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GDC-0449 (Vismodegib)
Hedgehog antagonist,potent and selective

GDC-0449 (Vismodegib)

Catalog No. A3021
Size Price Stock Qty
Evaluation Sample $28.00 In stock
10mg $50.00 In stock
50mg $65.00 In stock
200mg $110.00 In stock
500mg $220.00 In stock

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Sample solution is provided at 25 µL, 10mM.

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Chemical structure

GDC-0449 (Vismodegib)

Related Biological Data

GDC-0449
Gli-luciferase reporter activity of CH310T 1/2 cells transfected with indicated SMO constructs following a dose response of GDC-0449. Values were normalized to maximum activity levels and are mean±SD.

Biological Activity

Description Vismodegib (GDC-0449) is a potent, novel and specific inhibitor of hedgehog with IC50 of 3 nM and also inhibitor of P-gp with IC50 of 3.0 μM.
Targets Hedgehog          
IC50 3 nM          

Protocol

Cell experiment: [1]

Cell lines

AsPC-1, MIA PaCa-2, PANC-1 and Pancreatic CSC cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

10 μM, 72 hours

Applications

Inhibition of cell survival and induction of apoptosis was observed within 24 h following exposure to this drug, but was maximally noticed at 72 h. In all the cell lines, GDC-0449 induced apoptosis is a dose-dependent manner reaching up to 65%. By comparison, GDC-0449 was less effective in inducing apoptosis in CSCs.

Animal experiment: [2]

Animal models

Male CB17 SCID mice injected with MDA PCa 118b cells

Dosage form

Oral administration, 100 mg/kg, twice a day for 21 days

Application

Shh, Gli1, Gli2, Smo, Ptch1, and Sufu were analyzed by qRT-PCR in GDC-0449 treated and untreated groups. Stromal expression of Gli1 and Ptch1 was marginally lower in the treated group compared to the control. Given that Gli1 and Ptch1 are reliable markers of an active Hh pathway these results confirm the pharmacodynamic effect of GDC-0449. Expression of Gli2 and Shh followed the same trend. Tumor epithelial expression of Sufu was significantly lower in treated than in untreated controls. Immunohistochemical testing confirmed a decrease in Sufu expression in the tumor epithelium.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Singh B N, Fu J, Srivastava R K, et al. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One, 2011, 6(11): e27306.

[2] Karlou M, Lu J F, Wu G, et al. Hedgehog signaling inhibition by the small molecule smoothened inhibitor GDC-0449 in the bone forming prostate cancer xenograft MDA PCa 118b. The Prostate, 2012, 72(15): 1638-1647.

GDC-0449 (Vismodegib) Dilution Calculator

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Chemical Properties

Cas No. 879085-55-9 SDF Download SDF
Synonyms Vismodegib, GDC-0449, HhAntag691, GDC0449, GDC 0449
Chemical Name 2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Canonical SMILES CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
Formula C19H14Cl2N2O3S M.Wt 421.3
Solubility Soluble in DMSO > 10 mM Storage Desiccate at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Research Update

3. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS One. 2013 Jul 22;8(7):e70599. doi: 10.1371/journal.pone.0070599. Print 2013.
Abstract
Vismodegib is a hedgehog signaling pathway inhibitor that reduces apoptosis and TRAIL-mediated liver injury in an FFC-induced mouse model of NASH attenuating hepatic inflammation and fibrosis.
4. Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients. Clin Cancer Res. 2013 Jun 1;19(11):3059-67. doi: 10.1158/1078-0432.CCR-12-3829. Epub 2013 Apr 3.
Abstract
Effects of food on exposure of vismodegib, an FDA-approved anti-BCC drug, were explored in patients with advanced solid tumors.
5. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res. 2013 Jan 1;19(1):258-67. doi: 10.1158/1078-0432.CCR-12-1800. Epub 2012 Oct 18.
Abstract
The efficacy, safety and PKs of the combined therapy of vismodegib, a Hedgehog pathway inhibitor with anti-CRC activity, and standard mCRC treatment were assessed in a randomized trial.

Background

GDC-0449 (2-chloro-N-[4-chloro-3-pyridin-2-yl-phenyl]-4-methane-sulfonyl benzamide), discovered by high throughput screening of a small molecule compound library followed by subsequent optimization through medical chemistry, is a potent and selective inhibitor of hedgehog (Hh) signaling, a pathway regulating cell growth and differentiation associated in pathogenesis of several cancers. It binds to signaling by smoothened (SMO) and suppresses activation of downstream Hh target genes resulting in the inhibition of Hh signaling pathway. GDC-0449 exhibits anti-tumor activity in a mouse model of medulloblastoma as well as in primary human tumor cell xenograft models of colorectal cancer and pancreatic carcinoma and is currently being evaluated in research projects investigating refractory, locally advanced or metastatic solid tumors.

Reference

Patricia M. LoRusso, Charles M. Rudin, Josina C. Reddy, Raoul Tibes, Glen J. Weiss, Mitesh J. Borad, Christine L. Hann, Julie R. Brahmer, Ilsung Chang, Walter C. Darbonne, Richard A. Graham, Kenn L. Zerivitz, Jennifer A. Low, and Daniel D. Von Hoff. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in Patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17: 2502-2511