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GDC-0449 (Vismodegib)

Hedgehog antagonist,potent and selective CAS# 879085-55-9

GDC-0449 (Vismodegib)

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Chemical structure

GDC-0449 (Vismodegib)

3D structure

Chemical Properties of GDC-0449 (Vismodegib)

Cas No. 879085-55-9 SDF Download SDF
PubChem ID 24776445 Appearance Powder
Formula C19H14Cl2N2O3S M.Wt 421.3
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GDC-0449
Solubility DMSO : ≥ 50 mg/mL (118.68 mM)
Ethanol : 2.86 mg/mL (6.79 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
SMILES CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
Standard InChIKey BPQMGSKTAYIVFO-UHFFFAOYSA-N
Standard 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)
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.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of GDC-0449 (Vismodegib)

DescriptionVismodegib (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.
TargetsHedgehog    
IC503 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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Preparing Stock Solutions of GDC-0449 (Vismodegib)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3736 mL 11.868 mL 23.7361 mL 47.4721 mL 59.3401 mL
5 mM 0.4747 mL 2.3736 mL 4.7472 mL 9.4944 mL 11.868 mL
10 mM 0.2374 mL 1.1868 mL 2.3736 mL 4.7472 mL 5.934 mL
50 mM 0.0475 mL 0.2374 mL 0.4747 mL 0.9494 mL 1.1868 mL
100 mM 0.0237 mL 0.1187 mL 0.2374 mL 0.4747 mL 0.5934 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of GDC-0449 (Vismodegib)

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.

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Background on GDC-0449 (Vismodegib)

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

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References on GDC-0449 (Vismodegib)

Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms.[Pubmed:22087285]

PLoS One. 2011;6(11):e27306.

BACKGROUND: Recent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSCs). Therefore, the chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. GDC-0449 (Vismodegib), orally administrable molecule belonging to the 2-arylpyridine class, inhibits SHH signaling pathway by blocking the activities of Smoothened. The objectives of this study were to examine the molecular mechanisms by which GDC-0449 regulates human pancreatic CSC characteristics in vitro. METHODOLOGY/PRINCIPAL FINDINGS: GDC-0499 inhibited cell viability and induced apoptosis in three pancreatic cancer cell lines and pancreatic CSCs. This inhibitor also suppressed cell viability, Gli-DNA binding and transcriptional activities, and induced apoptosis through caspase-3 activation and PARP cleavage in pancreatic CSCs. GDC-0449-induced apoptosis in CSCs showed increased Fas expression and decreased expression of PDGFRalpha. Furthermore, Bcl-2 was down-regulated whereas TRAIL-R1/DR4 and TRAIL-R2/DR5 expression was increased following the treatment of CSCs with GDC-0449. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GDC-0449-treated pancreatic CSCs. Thus, activated Gli genes repress DRs and Fas expressions, up-regulate the expressions of Bcl-2 and PDGFRalpha and facilitate cell survival. CONCLUSIONS/SIGNIFICANCE: These data suggest that GDC-0499 can be used for the management of pancreatic cancer by targeting pancreatic CSCs.

Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.[Pubmed:21753154]

Clin Cancer Res. 2011 Sep 1;17(17):5774-82.

PURPOSE: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. EXPERIMENTAL DESIGN: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. RESULTS: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. CONCLUSIONS: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.

Emergence of chemoresistance in a metastatic basal cell carcinoma patient after complete response to hedgehog pathway inhibitor vismodegib (GDC-0449).[Pubmed:25117162]

Australas J Dermatol. 2014 Aug;55(3):218-21.

Vismodegib (GDC-0449, Genentech, USA), a small molecule inhibitor of the Hedgehog signalling pathway, has potent anti-tumour activity in advanced basal cell carcinoma (BCC). We report a case of a 67-year-old Australian man with metastatic BCC including pulmonary disease with malignant effusion who showed a dramatic complete response to vismodegib but subsequently experienced a recurrence of pulmonary disease, indicative of chemoresistance to vismodegib. This case is the first to illustrate chemoresistance in a patient with metastatic BCC, and demonstrates the need for closely monitoring metastatic BCC patients even after an apparently complete response.

Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma.[Pubmed:25278454]

Clin Cancer Res. 2014 Dec 1;20(23):5937-5945.

PURPOSE: The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449-mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity. RESULTS: On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade >/= 3 adverse events were noted in 56% of patients. CONCLUSION: We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer.

Description

Vismodegib (GDC-0449) is an orally active hedgehog pathway inhibitor with an IC50 of 3 nM. It also inhibits P-gp, ABCG2 with IC50 values of 3.0 μM and 1.4 μM, respectively.

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