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GDC-0449

Overactive Hedgehog (Hh) signaling may occur in cancer by 2 distinct mechanisms: ligand-dependent and mutation-driven (ligand-independent) signaling.^3,4 Aberrant activation of the Hh signaling pathway has been implicated in the development of many different types of cancer.^1,5

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).^4,7-9 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-0449.⁹

1. GDC-0449 is a small-molecule inhibitor designed to specifically inhibit SMO, a key mediator of the Hh signaling pathway.^1,7,9

   

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.^1,7,8

   

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.¹

   

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