Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic…

• WF
  Wenner-Gren Foundation
• JH
  Johns Hopkins University
• C
  Cancerfonden
• KI
  Karolinska Institutet
• US
  Universität Salzburg
• SB
  Swiss Bridge Foundation
• NC
  National Cancer Institute