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[摘要]：When it became apparent that aberrant hedgehog (HH) pathway signaling was a likely mediator in the development of tumors, especially basal cell carcinoma, many companies began to investigate the use of small-molecule inhibitors of key steps in the HH pathway as potential anticancer agents. Under normal physiological conditions the pathway controls embryonic development via HH ligand binding to the patched (PTC) receptor, which inhibits a second receptor, smoothened (SMO), which in turn regulates glioma-associated oncogene (GLI)-mediated transcription of pro- and antiapoptotic genes. Genentech and Curls developed vismodegib (GDC-0449), a small-molecule inhibitor of SMO, which was proven to be the first such compound to successfully target tumorigenesis in humans. In preclinical pharmacokinetic and pharmacodynamic studies, vismodegib demonstrated promising characteristics for use in humans, more so than its predecessor Hh-Antag691. Vismodegib successfully entered phase I clinical trials in patients with basal cell carcinoma and medulloblastoma, and is currently under investigation in a number of phase II trials for various cancers, including basal cell carcinoma, medulloblastoma, pancreatic, ovarian, stomach and breast cancers, in addition to a number of phase II trials investigating its use in combination with other chemotherapeutic agents such as bevacizumab. |
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