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Vismodegib (GDC-0449)

Overactive Hedgehog (Hh) signaling may occur in cancer by 2 distinct mechanisms: ligand-dependent and mutation-driven (ligand-independent) signaling.1,2 Aberrant activation of the Hh signaling pathway has been implicated in the development of many different types of cancer.3,4

Emerging preclinical evidence suggests that tumor growth occurring in mutation-driven models and of ligand overexpression models can be inhibited by blocking key components of the pathway, such as Smoothened (SMO).2,5-7 GDC-0449 was discovered by Genentech and was jointly validated with Curis, Inc. through a series of preclinical studies. Genentech and Roche are responsible for the clinical development and commercialization of GDC-0449.7

GA101
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  1. GDC-0449 is a small-molecule inhibitor designed to specifically inhibit SMO, a key mediator of the Hh signaling pathway.3,5,7

    GDC-0449 Vignette 1

  2. In preclinical models, GDC-0449 inhibits overactive SMO signaling and tumor growth driven by mutations or by elevated levels of Hh ligands, offering the potential for broad application.3,5,7

    GDC-0449 Vignette 2

  3. When SMO signaling is inhibited, the transcription factor GLI remains inactive, thus preventing the expression of genes that mediate the role of Hh on tumor growth.3

    GDC-0449 Vignette 3

References:
1.
Evangelista M, Tian H, de Sauvage FJ. The Hedgehog signaling pathway in cancer. Clin Cancer Res. 2006;12:5924-5928.
2.
Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406-410.
3.
Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5:1026-1033.
4.
Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303-312.
5.
Williams JA, Guicherit OM, Zaharian BI, et al. Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A. 2003;100:4616-4621.
6.
Romer JT, Kimura H, Magdaleno S, et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/-p53-/- mice. Cancer Cell. 2004;6:229-240.
7.
Robarge KD, Brunton SA, Castanedo GM, et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009;19:5576-5581.