A3021-200mg | GDC-0449 (Vismodegib) [879085-55-9] Clinisciences

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. 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
2. 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.
3. 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
4. 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
5. 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
6. 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

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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]
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.
Reaction Conditions	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
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.
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.

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

Chemical structure

Related Biological Data

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.