Abstract
Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Drug Discovery
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Hedgehog Proteins / metabolism*
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Humans
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Lactams / metabolism
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Lactams / pharmacology*
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Lactones / metabolism
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Lactones / pharmacology*
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Mice
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Patched Receptors
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Signal Transduction / drug effects*
Substances
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Hedgehog Proteins
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Lactams
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Lactones
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Patched Receptors
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Receptors, Cell Surface
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robotnikinin
Associated data
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PubChem-Substance/56431959
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PubChem-Substance/56431960
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PubChem-Substance/56431961
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PubChem-Substance/56431962
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PubChem-Substance/56431963
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PubChem-Substance/56431964
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PubChem-Substance/56431965
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PubChem-Substance/56431966
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PubChem-Substance/56431967
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PubChem-Substance/56431968
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PubChem-Substance/56431969
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PubChem-Substance/56431970
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PubChem-Substance/56431971
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PubChem-Substance/56431972
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PubChem-Substance/56431973
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PubChem-Substance/56431974
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PubChem-Substance/56431975
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PubChem-Substance/56431976
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PubChem-Substance/56431977
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PubChem-Substance/56431978
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PubChem-Substance/56431979
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PubChem-Substance/56431980