Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
Mol Pharmacol. 2010 Sep;78(3):486-96. doi: 10.1124/mol.110.066431. Epub 2010 Jun 17.
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.
最近，我们鉴定出 GANT61，这是一种Gli 转录因子的小分子拮抗剂，Gli 转录因子是哺乳动物 Hedgehog（HH）信号通路的最终效应物。在这里，我们描述了 GANT61 的一个二胺亚结构，它具有生物活性，并表明该分子的这一部分在结构上与反式-1,4-双（2-氯苯甲脒基）环己烷二盐酸盐（AY9944）有关，AY9944 是一种酶活性抑制剂和 7-脱氢胆固醇还原酶（Dhcr7，EC 1.3.1.21）的转录诱导剂。用 GANT61 二胺、AY9944 或过表达 Dhcr7 处理细胞，会导致 Smoothened 依赖性和非依赖性 HH 信号转导减弱。虽然 GANT61 的功能不依赖于 Dhcr7，但 AY9944 需要上调内源性 Dhcr7。这些发现表明，调节 Dhcr7 的抗精神病药（氯氮平、氯丙嗪、氟哌啶醇）和抗抑郁药（丙咪嗪）在体外和体内调节 HH 信号转导。HH 信号转导的调节可能代表了治疗精神分裂症和抑郁症的药物迄今未被发现的生物学（副作用）。
