A small molecule that binds Hedgehog and blocks its signaling in human cells.
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.
Stanton
Benjamin Z
BZ
Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Peng
Lee F
LF
Maloof
Nicole
N
Nakai
Kazuo
K
Wang
Xiang
X
Duffner
Jay L
JL
Taveras
Kennedy M
KM
Hyman
Joel M
JM
Lee
Sam W
SW
Koehler
Angela N
AN
Chen
James K
JK
Fox
Julia L
JL
Mandinova
Anna
A
Schreiber
Stuart L
SL
D016475:3T3 Cells; D000818:Animals; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007769:Lactams / Q000378:metabolism / Q000494:pharmacology*; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D053823:Hedgehog Proteins; D007769:Lactams; D007783:Lactones; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C539164:robotnikinin