Robotnikinin: small molecule inhibitor of sonic hedgehog (Shh) signaling in human cells
A small molecule that binds Sonic hedgehog (Shh) protein and blocks Shh signaling in human cells
Sonic hedgehog (Shh), the most widely characterized of the Hedgehog homologs, is essential for proper embryonic development and plays important roles in many cancers. The discovery of small-molecule modulators of Shh signaling provides an avenue to regulate the activity of a pathway implicated in medulloblastoma, basal cell carcinoma, pancreatic cancer, prostate cancer and developmental disorders. Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. None of the reported synthetic Shh pathway inhibitors are known to target the extracellular protein Shh protein itself. Therefore, scientists at Harvard University use a target-based discovery method to provide a new approach to identify novel modulators of upstream Shh signaling.
Innovations and Advantages
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 in a dose-dependent manner. The IC50 of robotnikinin is approximately 3 uM in the Shh-LIGHT2 cell line, an NIH3T3 line transformed with a Gli-luciferase construct which has been widely used to study Shh signaling.
Robotnikinin inhibits the induction of the Shh pathway. The discovery of robotnikinin has provided a powerful small molecule probe of an important signaling pathway involving a step in the pathway not previously accessible to small-molecule modulation. Robotnikinin will be especially valuable as a probe of diseases associated with aberrant Shh pathway activity.
Intellectual Property Status: Patent pending
Benjamin Z Stanton, Lee F Peng, Nicole Maloof, Kazuo Nakai, Xiang Wang, Jay L Duffner, Kennedy M Taveras, Joel M Hyman, Sam W Lee, Angela N Koehler, James K Chen, Julia L Fox, Anna Mandinova, Stuart L Schreiber. 2009. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nature Chemical Biology 5, 154 ? 156.
Buhrlage, Sara Jean
Fox, Julia L.
Macpherson, Lawrence J.
Peng, Lee F.
Schreiber, Stuart L.
Stanton, Benjamin Z.
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Reference Harvard Case #3216