Hedgehog (Hh) is composed of N-terminal and C-terminal domains that dissociate in a self-catalyzed proteolytic cleavage reaction. The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Hedgehog signaling pathway is linked to tumorigenesis and is aberrantly activated in a variety of cancers. Hh ligands bind to and suppress the transmembrane receptor Patched (PTCH). It suppresses Smoothened (SMO), a seven-transmembrane-helix protein that positively regulates the Hh pathway. Mammals have three Hedgehog homologues, Desert (DHH), Indian (IHH), and Sonic (SHH). Sonic hedgehog (Shh) is a morphogen essential to the developing nervous system. And Shh continues to play an important role in adult life by contributing to cell proliferation and differentiation. It maintains blood-brain barrier integrity, and being cytoprotective against oxidative and excitotoxic stress.

Vismodegib (also known as GDC-0449) is a potent and orally active hedgehog (Hh) pathway inhibitor.

First, Vismodegib blocks the function of Smoothened and it can eliminate medulloblastoma in both Ptc1+/-p53-/- and Cxcr6 mutant mice. Second, Vismodegib is a potent two ATP-binding cassette (ABC) transporters, ABCG2/BCRP and ABCB1/Pgp inhibitor, and is a mild ABCC1/MRP1 inhibitor. Third, Vismodegib penetrates the blood-brain barrier well. In addition, Vismodegib reverses the resistance of NCI-H460 human non-Small Cell lung carcinoma cells to cytotoxic agents that are substrates of ABCG2.

Importantly, Vismodegib shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. Specifically, Vismodegib shows favorable pharmacokinetics in preclinical species characterized by moderate clearance in monkeys and low to very low clearance in mouse, rat, and dog. Vismodegib has the potential for the research of metastatic or locally advanced basal cell carcinoma and metastatic medulloblastoma.

In summary, Vismodegib is an orally active hedgehog (Hh) pathway and ABC transporters inhibitor, with strong antitumor activity.


[1] Yimao Zhang, et al. Neoplasia. 2009 Jan;11(1):96-101.

[2] Harvey Wong, et al. Clin Cancer Res. 2011 Jul 15;17(14):4682-92.