Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions.
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.
Williams
Juliet A
JA
Curis Incorporated, 61 Moulton Street, Cambridge, MA 02138, USA.
Guicherit
Oivin M
OM
Zaharian
Beatrice I
BI
Xu
Yin
Y
Chai
Ling
L
Wichterle
Hynek
H
Kon
Charlene
C
Gatchalian
Christine
C
Porter
Jeffery A
JA
Rubin
Lee L
LL
Wang
Frank Y
FY
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002642:Chick Embryo; D004149:Dioxoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D053823:Hedgehog Proteins; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines / Q000494:pharmacology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014704:Veratrum Alkaloids / Q000494:pharmacology
D000970:Antineoplastic Agents; C474318:CUR 61414; D004149:Dioxoles; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C010206:jervine