Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade Export

@article{citeulike:5631929, abstract = {10.1073/pnas.0907134106 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.}, author = {Hyman, Joel M. and Firestone, Ari J. and Heine, Vivi M. and Zhao, Yun and Ocasio, Cory A. and Han, Kyuho and Sun, Mark and Rack, Paul G. and Sinha, Surajit and Wu, Jason J. and Solow-Cordero, David E. and Jiang, Jin and Rowitch, David H. and Chen, James K.}, citeulike-article-id = {5631929}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0907134106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/33/14132.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/33/14132.full.pdf}, day = {18}, doi = {10.1073/pnas.0907134106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {signaling}, month = {August}, number = {33}, pages = {14132--14137}, posted-at = {2009-08-24 16:03:14}, priority = {2}, title = {Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade}, url = {http://dx.doi.org/10.1073/pnas.0907134106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5631929 L3 - citeulike-article-id:5631929 N2 - 10.1073/pnas.0907134106 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. IS - 33 JF - Proceedings of the National Academy of Sciences EP - 14137 TI - Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade VL - 106 SP - 14132 KW - signaling AU - Hyman, Joel AU - Firestone, Ari AU - Heine, Vivi AU - Zhao, Yun AU - Ocasio, Cory AU - Han, Kyuho AU - Sun, Mark AU - Rack, Paul AU - Sinha, Surajit AU - Wu, Jason AU - Solow-Cordero, David AU - Jiang, Jin AU - Rowitch, David AU - Chen, James PY - 2009/08/18/ UR - http://dx.doi.org/10.1073/pnas.0907134106 ER -