Abstract
Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase (Dhcr7, EC 1.3.1.21). Treatment of cells with the GANT61 diamine, AY9944, or overexpression of DHCR7 results in the attenuation of Smoothened-dependent and -independent HH signaling. Whereas GANT61 function is independent of Dhcr7, AY9944 does require up-regulation of endogenous Dhcr7. In line with these findings, Dhcr7-modulating antipsychotic (clozapine, chlorpromazine, haloperidol) and antidepressant (imipramine) drugs regulate HH signaling in vitro and in vivo. Modulation of HH signaling may represent a hitherto undiscovered biological (side) effect of therapeutics used to treat schizophrenia and depression.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.This study was supported by the Swedish Cancer Society; the Swedish Research Council; Swiss Bridge; the Wenner-Gren-Foundation; the Lars Hiertas Minne Foundation; the Karolinska Institutet; and LOEWE (Tumor and Inflammation).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.066431.
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ABBREVIATIONS:
- HH
- Hedgehog
- Dhcr7
- 7-dehydrocholesterol-reductase
- GANT61
- Gli-antagonist 61
- AY9944
- trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride
- Ptch1
- Patched 1 receptor
- Smo
- Smoothened
- SAG
- Smoothened agonist
- Sufu
- Suppressor of Fused
- 7-DHC
- 7-dehydrocholesterol
- SLOS
- Smith-Lemli-Opitz syndrome
- SREBP
- sterol regulatory element-binding protein
- MEF
- mouse embryonic fibroblast
- DMEM
- Dulbecco's modified Eagle's medium
- PCR
- polymerase chain reaction
- TPA
- 12-O-tetradecanoylphorbol-13-acetate
- QPCR
- quantitative polymerase chain reaction
- PBS
- phosphate-buffered saline
- DMSO
- dimethyl sulfoxide
- SANT1
- N-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methylene]-4- (phenylmethyl)-1-piperazinamine
- siRNA
- small interfering RNA
- SSD
- sterol-sensing domain.
- Received May 17, 2010.
- Accepted June 17, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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