Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade.
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.
Hyman
Joel M
JM
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Firestone
Ari J
AJ
Heine
Vivi M
VM
Zhao
Yun
Y
Ocasio
Cory A
CA
Han
Kyuho
K
Sun
Mark
M
Rack
Paul G
PG
Sinha
Surajit
S
Wu
Jason J
JJ
Solow-Cordero
David E
DE
Jiang
Jin
J
Rowitch
David H
DH
Chen
James K
JK
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004843:Epistasis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding
D053823:Hedgehog Proteins