The hedgehog(Hh) signaling pathway is one of the key regulators of animal development and is present in all bilaterians. The Hh family of proteins have since been recognized to involve in many fundamental processes in vertebrate embryonic development and play an important role in regulating cell fate, patterning, proliferation, survival and differentiation of many different regions. In the embryonic period, dysfunction in the Hh signaling pathway will lead to brain, facial and other midline defects such as holoprosencephaly, cyclopia, absent nose or cleft palate.
In adults, the Hh signaling pathway is still active and contributes to regulation of tissue repair and renewal. However, disorder of this pathway will cause abnormal cell proliferation and differentiation and thus result in tumorigenesis or tumor develooment in a variety of tissues.
Accordingly, the Hh signaling pathway has also recently been considered as a therapeutic target in cancers. Cyclopamine is the first found Hh pathway inhibitor to induce cyclopia and holoprosencephaly in lambs. Subsequently, many novel and more potent derivatives have been synthesized with greater oral bioavailability, including SANT1-SANT4, CUR-61414, HhAntag-691 and GDC-0449. And the inhibitors are demonstrated to produce the inhibitory effects by suppressing the transmembrane receptor protein Smoothened (SMO).
There are three basic models which is observed for Hh pathway activity in cancers: ligand independent, mutation driven; autocrine, ligand dependent; paracrine, ligand dependent. According to the differences of causes, different target inhibitors are needed for treatment.
At present, the advances of Hh pathway inhibitors have been constantly reported in the ongoing preclinical and clinical trials, thus Hh pathway inhibitors represent an important new class of therapeutic agents in the treatment of cancers.
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