>>Published online before print April 4, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0732813100
Developmental Biology
Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions
Juliet A. Williams *, Oivin M. Guicherit *, Beatrice I. Zaharian *, Yin Xu *, Ling Chai *, Hynek Wichterle , Charlene Kon , Christine Gatchalian *, Jeffery A. Porter *, Lee L. Rubin *¶, and Frank Y. Wang *
*Curis Incorporated, 61 Moulton Street, Cambridge, MA 02138; Hammer Health Sciences Center, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, 10th Floor, New York, NY 10032; and Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305
Edited by Anthony P. Mahowald, University of Chicago, Chicago, IL, and approved February 12, 2003 (received for review May 10, 2002)
The link between basal cell carcinoma (BCC) and aberrant activation of the Hedgehog (Hh) signaling pathway has been well established in humans and in mouse models. Here we report the development of assays, including two novel in vitro BCC models, which allowed us to screen for Hh inhibitors and test their validity as potential treatments for BCC. We identified a novel small molecule Hh inhibitor (CUR61414) that can block elevated Hh signaling activity resulting from oncogenic mutations in Patched-1. Moreover, CUR61414 can suppress proliferation and induce apoptosis of basaloid nests in the BCC model systems, whereas having no effect on normal skin cells. These findings directly demonstrate that the use of Hh inhibitors could be a valid therapeutic approach for treating BCC.<<
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