Vismodegib

Vismodegib (trade name Erivedge /ˈɛrɪvɛdʒ/ ERR-i-vej) is a drug for the treatment of basal-cell carcinoma (BCC). 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.[2] 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.[3] The drug was developed by the biotechnology/pharmaceutical company Genentech.[2]

Vismodegib
Clinical data
Pronunciation/ˌvɪsmoʊˈdɛɡɪb/
VIS-moh-DEG-ib
Trade namesErivedge
Other namesGDC-0449, RG-3616
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth (capsules)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability31.8%
Protein binding>99%
Metabolism<2% metabolised by CYP2C9, CYP3A4, CYP3A5
Elimination half-life4 days (continuous use),
12 days (single dose)
ExcretionFecal (82%), Urinary (4.4%)
Identifiers
IUPAC name
  • 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.234.019
Chemical and physical data
FormulaC19H14Cl2N2O3S
Molar mass421.29 g·mol−1
3D model (JSmol)
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 patients 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.[2][4]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the Hedgehog signaling pathway.[3] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[6]

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). The effects were mostly mild to moderate.[1]

Development

Vismodegib has undergone several promising phase I and phase II clinical trials for its use in treating medulloblastoma.[7]

See also
  • Cyclopamine, a naturally occurring SMO antagonist

References
  1. FDA Professional Drug Information
  2. "FDA approves Erivedge (vismodegib) capsule, the first medicine for adults with advanced basal cell carcinoma". Roche. 30 January 2012. Retrieved 9 August 2020.
  3. "Molecule of the Month". June 2011. {{cite journal}}: Cite journal requires |journal= (help)
  4. Lacroix M (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
  5. "Vismodegib (GDC-0449) Smoothened Inhibitor - BioOncology".
  6. Spreitzer H (4 July 2011). "Neue Wirkstoffe – Vismodegib". Österreichische Apothekerzeitung (in German) (14/2011): 10.
  7. Li, Y; Song, Q; Day, BW (30 July 2019). "Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis". Acta Neuropathologica Communications. 7 (1): 123. doi:10.1186/s40478-019-0773-8. PMC 6668073. PMID 31362788.

Further reading
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