The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade
Open accessAbstract
Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.
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Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome
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Vertebrate Smoothened functions at the primary cilium
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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
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Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened
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Self-citationPatched1 Regulates Hedgehog Signaling at the Primary Cilium
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Activating Smoothened mutations in sporadic basal-cell carcinoma
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Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine
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Self-citationWidespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours
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Cited by
Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways
Takebe, N., Harris, P. J., Warren, R. Q., & Ivy, S. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.196 · Cited by 992
Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein
Firestone, A. J., Weinger, J. S., Maldonado, M., Barlan, K., Langston, L. D., O’Donnell, M., Gelfand, V. I., Kapoor, T. M., & Chen, J. K. (2012) · Nature · doi:10.1038/nature10936 · Cited by 403
Self-citationPietrobono, S., Gagliardi, S., & Stecca, B. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00556 · Cited by 303
Chen, Y., Sasai, N., Ma, G., Yue, T., Jia, J., Briscoe, J., & Jiang, J. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001083 · Cited by 225
Self-citationA Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia
Dorn, K. V., Hughes, C. E., & Rohatgi, R. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.07.004 · Cited by 174
Metadata
- Authors
- Hyman, J. M., Firestone, A. J., Heine, V. M., Zhao, Y., Ocasio, C. A., Han, K., Sun, M., Rack, P. G., Sinha, S., Wu, J. J., Solow-Cordero, D. E., Jiang, J., Rowitch, D. H., & Chen, J. K.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-08-18
- Volume
- 106
- Issue
- 33
- Pages
- 14132-14137
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2153260902
- Cited by
- 305
- References
- 43
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- green
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- Hyman, J. M., Firestone, A. J., Heine, V. M., Zhao, Y., Ocasio, C. A., Han, K., Sun, M., Rack, P. G., Sinha, S., Wu, J. J., Solow-Cordero, D. E., Jiang, J., Rowitch, D. H., & Chen, J. K. (2009). Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0907134106
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