title: Discovery and preclinical development of vismodegib.
abstract: BACKGROUND
  Vismodegib is the first Hedgehog (Hh) pathway inhibitor approved in the US for the treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC). It was approved by the US FDA on 30 January 2012, and by the European Commission on 12 July 2013, for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. Vismodegib selectively inhibits the Hh signaling pathway, binding to and inhibiting a critical signal-transducing component of the pathway, Smoothened (SMO). Vismodegib was discovered by Genentech, Inc., under a collaboration agreement with Curis, Inc.
  
  
  METHODS
  This article reviews the development of vismodegib from its discovery, preclinical pharmacology and validation to the clinical pharmacokinetics and validation in Phase I and II clinical investigations. We also provide a survey of other Hh pathway inhibitors in clinical development.
  
  
  CONCLUSIONS
  The authors' experience in target-based drug discovery suggests that vismodegib's path to the clinic deserves some reflection to identify key steps that have contributed to its success. Targeting the Hh pathway with vismodegib blocks the abberant signaling caused by mutational inactivation of the negative regulator PTCH1 or mutational activation of SMO. Vismodegib gives physicians a treatment option for patients with locally advanced or metastatic BCC for whom surgery or radiation is not recommended.
authors.affiliation: Translational Oncology, Genentech, Inc. , 1 DNA Way, South San Francisco, CA , USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
mesh_terms: D000328:Adult; D000813:Anilides / Q000266:history / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000266:history / Q000493:pharmacokinetics / Q000494:pharmacology; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D055808:Drug Discovery / Q000266:history; D049674:History, 21st Century; D006801:Humans; D011725:Pyridines / Q000266:history / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C538724:HhAntag691; D011725:Pyridines
keywords: Erivedge™; GDC-0449; GLI1; Gorlin’s syndrome; Hedgehog pathway inhibitor; Hedgehog signaling pathway; Patched 1; Smoothened; basal cell carcinoma; targeted cancer therapy; vismodegib