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
- 1. Tiago Rito, Ashley R. G. Libby, et al. "Timely TGFβ signalling inhibition induces notochord." nature. 18 December 2024
- 2. Yi Sui, Teng Wang, et al. "Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor." Cancer Res. 2024 May 22. PMID: 38775809
- 3. Yu Shi, et al. "Gli1 labels progenitors during chondrogenesis in postnatal mice." EMBO Rep. 2024 Apr;25(4):1773-1791. PMID: 38409269
- 4. Yakinthi Chrisochoidou, Rajat Roy, et al. "Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells." Cell Death Dis. 2023 Nov 8;14(11):725. PMID: 37938546
- 5. Yuan Han Teh, Rui Jing, et al. "More than just a KRAS inhibitor: DCAI abrogates the self-renewal of pancreatic cancer stem cells in vitro."Oncologie. September 27, 2023.
- 6. Qing Gao, Xuhong Chang, et al. "LncRNA MEG3 restrained pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway‐mediated autophagy." Environ Toxicol. 2022 Jan;37(1):79-91. PMID: 34608745
- 7. Su-Fen Wei, Dan-Hua He, et al. "Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma." Biochem Pharmacol. 2021 Aug;190:114593. PMID:33964282
- 8. Kowolik CM, Lin M, et al. "Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer." J Exp Clin Cancer Res. 2019 Oct 28;38(1):431. PMID:31661013
- 9. Lima-Fernandes E, Murison A, et al. "Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells." Nat Commun. 2019 Mar 29;10(1):1436. PMID:30926792
| Physical Appearance | A solid |
| Storage | Desiccate at -20°C |
| M.Wt | 421.3 |
| Cas No. | 879085-55-9 |
| Formula | C19H14Cl2N2O3S |
| Synonyms | Vismodegib, GDC-0449, HhAntag691, GDC0449, GDC 0449 |
| Solubility | ≥21.08 mg/mL in DMSO; insoluble in H2O; ≥4.96 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | 2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide |
| SDF | Download SDF |
| Canonical SMILES | CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment: [1] | |
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Cell lines |
AsPC-1, MIA PaCa-2, PANC-1 and Pancreatic CSC cells |
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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. |
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Reaction Conditions |
10 μM, 72 hours |
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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] | |
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Animal models |
Male CB17 SCID mice injected with MDA PCa 118b cells |
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Dosage form |
Oral administration, 100 mg/kg, twice a day for 21 days |
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Applications |
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. |
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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. |
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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. |
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| 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 | |||||
Quality Control & MSDS
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