Vismodegib

Vismodegib, sold under the brand name Erivedge, is a medication used for the treatment of basal-cell carcinoma (BCC).^[2] The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.^[3] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011^[update].^[4] The drug was developed by the biotechnology/pharmaceutical company Genentech.^[3]

Vismodegib

Clinical data
Pronunciation	/ˌvɪsmoʊˈdɛɡɪb/ VIS-moh-DEG-ib
Trade names	Erivedge
Other names	GDC-0449, RG-3616
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN US FDA: Vismodegib
Pregnancy category	AU: X (High risk)[1]
Routes of administration	By mouth
ATC code	L01XJ01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only UK: POM (Prescription only) US: ℞-only[2] EU: Rx-only
Pharmacokinetic data
Bioavailability	31.8%
Protein binding	>99%
Metabolism	<2% metabolised by CYP2C9, CYP3A4, CYP3A5
Elimination half-life	4 days (continuous use), 12 days (single dose)
Excretion	Fecal (82%), Urinary (4.4%)
Identifiers
IUPAC name 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
CAS Number	879085-55-9
PubChem CID	24776445
IUPHAR/BPS	6975
DrugBank	DB08828
ChemSpider	23337846
UNII	25X868M3DS
KEGG	D09992
ChEBI	CHEBI:66903 Y
ChEMBL	ChEMBL473417
CompTox Dashboard (EPA)	DTXSID40236689
ECHA InfoCard	100.234.019
Chemical and physical data
Formula	C19H14Cl2N2O3S
Molar mass	421.29 g·mol−1
3D model (JSmol)	Interactive image
SMILES CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
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) Key:BPQMGSKTAYIVFO-UHFFFAOYSA-N

Indication

Vismodegib is indicated for people with basal-cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.^[3][5]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the Hedgehog signaling pathway.^[4] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.^[6] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.^[7]

Side effects

In clinical trials, common side effects included gastrointestinal disorders (nausea, vomiting, diarrhoea, constipation), muscle spasms, fatigue, hair loss, and dysgeusia (distortion of the sense of taste).^[2]

Development

Vismodegib has undergone several promising phase I and phase II clinical trials for its use in treating medulloblastoma.^[8]