Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened (Efficient Drug Screening for Thousands of Protein Targets)

Opportunity I: Dysregulation of the Sonic hedgehog-Patched-Gli pathway leads to several human diseases. Disruptions in this pathway during embryogenesis are associated with birth defects. In adults, aberrant hedgehog (Hh) pathway activation is associated with several cancers, including medulloblastoma and basal cell carcinoma, and many of these tumors involve mutations in Patched (Ptch) or Smoothened. The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog. Recently, investigators at Johns Hopkins identified the mechanism by which cyclopamine mediates this effect; cyclopamine inhibits Hedgehog signaling by binding to and inhibiting the activities of Smoothened. Opportunity II: A significant problem in pharmaceutical discovery is that there are a large number of potential protein targets and a very large number of distinct drug-like small molecules to be screened. While there are multiple strategies available for the identification of small molecule ligands for individual protein targets, scientists at Johns Hopkins have devised a novel method by which chemical ligands for cellular proteins may be rapidly identified on a genomic scale using flow cytometry to identify interactions in single cells. Proof of the concept behind this method was shown in experiments that used cell sorting to demonstrate the binding of fluorescently tagged cyclopamine to Smoothened over-expressed in COS cells. Description (Set) Proposed Use (Set) These findings validate Smoothened as a therapeutic target in the treatment of Hedgehog-related diseases. The screening method described in this invention may allow a 100-10,000-fold increase in speed and decrease in cost when compared to individually screening pharmacologically relevant targets.

Inventor(s): Beachy, Philip A.

Type of Offer: Licensing

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