Selective Identification of Hedgehog Pathway Antagonists by Direct Analysis of Smoothened Ciliary Translocation

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Selective Identification of Hedgehog Pathway Antagonists by Direct Analysis of Smoothened Ciliary Translocation

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dc.contributor.author Wang, Yu
dc.contributor.author Davidow, Lance Steven
dc.contributor.author Blanchard, Joel
dc.contributor.author Lam, Kelvin
dc.contributor.author Yoo, Jin Woo
dc.contributor.author Coy, Shannon
dc.contributor.author McMahon, Andrew P.
dc.contributor.author Rubin, Lee L.
dc.contributor.author Arvanites, Anthony C.
dc.date.accessioned 2012-05-11T19:40:24Z
dc.date.issued 2012-05-11
dc.identifier.citation Wang, Yu, Anthony C. Arvanites, Lance Steven Davidow, Joel Blanchard, Kelvin Lam, Jin Woo Yoo, Shannon Coy, Lee L. Rubin, and Andrew P. McMahon. 2012. Selective identification of hedgehog pathway antagonists by direct analysis of smoothened ciliary translocation. ACS Chemical Biology 7(6): 1040–1048. en_US
dc.identifier.issn 1554-8929 en_US
dc.identifier.issn 1554-8937 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8730547
dc.description.abstract Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo’s actions. Smo ciliary translocation is inhibited by some pathway antagonists, while others promote ciliary accumulation, an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG and impaired by a mutation that generates a ligand-independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition and inhibited SmoM2 at concentrations similar to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies. en_US
dc.description.sponsorship Molecular and Cellular Biology en_US
dc.description.sponsorship Stem Cell and Regenerative Biology en_US
dc.language.iso en_US en_US
dc.publisher American Chemical Society en_US
dc.relation.isversionof doi:10.1021/cb300028a en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pubmed/22554036 en_US
dash.license OAP
dc.title Selective Identification of Hedgehog Pathway Antagonists by Direct Analysis of Smoothened Ciliary Translocation en_US
dc.type Journal Article en_US
dc.description.version Author's Original en_US
dc.relation.journal ACS Chemical Biology en_US
dash.depositing.author McMahon, Andrew P.
dc.date.available 2012-05-11T19:40:24Z

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  • FAS Scholarly Articles [6929]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University

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