Scaffold hopping approach to a new series of smoothened antagonists

The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization.

Graphical abstractThe hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization.Figure optionsDownload full-size imageDownload as PowerPoint slide