EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73412_C
Hedgehog通路激活剂；激活Smoothened（SMO）
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总览
SAG （Smoothened Agonist）是一种含氯苯并噻吩的化合物，作为G蛋白偶联受体Smoothened（SMO, EC₅₀=3 nM；Chen et al.）的激活剂。SMO是Hedgehog信号通路的组成部分，在Patched受体受到Hedgehog家族配体刺激后，SMO会转位至初级纤毛，从而激活通路。SAG通过直接结合七螺旋束（Kd=59 nM）来激活SMO ，从而稳定纤毛中SMO的特定构象，并导致下游基因表达增加（Rohatgi et al.）。SAG可消除环巴胺对SMO的抑制作用，表明其作用于环巴胺的下游（Frank-Kamenetsky et al.; Chen et al.; Lewis & Krieg）。
分化
·促进人诱导多能干细胞的神经元分化（Mak et al.）。
维持培养
·在体内和体外诱导神经元和神经胶质前体的增殖和存活（Bragina et al.）。
·防Math1-Cre、SmoM2转基因小鼠的糖皮质激素神经毒性（Heine et al.）。
·挽救唐氏综合征Ts65Dn小鼠模型的小脑大小和行为表型（Das et al.）。
细胞类型
神经细胞，PSC衍生，神经干/祖细胞，多能干细胞
种属
人，小鼠，非人灵长类，其他物种，大鼠
应用
分化，扩增，培养
研究领域
疾病建模，神经科学，干细胞生物学
CAS 编号
912545-86-9
化学式
C₂₈H₂₈ClN₃OS
纯度
≥98%
通路
Hedgehog
靶点
SMO
产品说明书及文档
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应用领域
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相关材料与文献
技术资料 (2)
文献 (8)
Small molecule modulation of Smoothened activity.
Proceedings of the National Academy of Sciences of the United States of America 2002 oct
Abstract
Smoothened (Smo),a distant relative of G protein-coupled receptors,mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear,the direct inhibition of Smo by cyclopamine,a plant-derived steroidal alkaloid,suggests that endogenous small molecules may be involved. Here we demonstrate that SAG,a chlorobenzothiophene-containing Hh pathway agonist,binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition,we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.
Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
Journal of biology 2002
Abstract
BACKGROUND: The Hedgehog (Hh) signaling pathway is vital to animal development as it mediates the differentiation of multiple cell types during embryogenesis. In adults,Hh signaling can be activated to facilitate tissue maintenance and repair. Moreover,stimulation of the Hh pathway has shown therapeutic efficacy in models of neuropathy. The underlying mechanisms of Hh signal transduction remain obscure,however: little is known about the communication between the pathway suppressor Patched (Ptc),a multipass transmembrane protein that directly binds Hh,and the pathway activator Smoothened (Smo),a protein that is related to G-protein-coupled receptors and is capable of constitutive activation in the absence of Ptc. RESULTS: We have identified and characterized a synthetic non-peptidyl small molecule,Hh-Ag,that acts as an agonist of the Hh pathway. This Hh agonist promotes cell-type-specific proliferation and concentration-dependent differentiation in vitro,while in utero it rescues aspects of the Hh-signaling defect in Sonic hedgehog-null,but not Smo-null,mouse embryos. Biochemical studies with Hh-Ag,the Hh-signaling antagonist cyclopamine,and a novel Hh-signaling inhibitor Cur61414,reveal that the action of all these compounds is independent of Hh-protein ligand and of the Hh receptor Ptc,as each binds directly to Smo. CONCLUSIONS: Smo can have its activity modulated directly by synthetic small molecules. These studies raise the possibility that Hh signaling may be regulated by endogenous small molecules in vivo and provide potent compounds with which to test the therapeutic value of activating the Hh-signaling pathway in the treatment of traumatic and chronic degenerative conditions.
Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process.
Proceedings of the National Academy of Sciences of the United States of America 2009
Abstract
The Hedgehog (Hh) signaling pathway controls growth,cell fate decisions,and morphogenesis during development. Damage to Hh transduction machinery can lead to birth defects and cancer. The transmembrane protein Smoothened (Smo) relays the Hh signal and is an important drug target in cancer. Smo enrichment in primary cilia is thought to drive activation of target genes. Using small-molecule agonists and antagonists to dissect Smo function,we find that Smo enrichment in cilia is not sufficient for signaling and a distinct second step is required for full activation. This 2-step mechanism--localization followed by activation--has direct implications for the design and use of anticancer therapeutics targeted against Smo.
更多信息
| 物种 | 人, 其它物种, 大鼠, 小鼠, 非人灵长类 |
|---|---|
| Cas Number | 912545-86-9 |
| Chemical Formula | C₂₈H₂₈ClN₃OS |
| 纯度 | ≥ 98% |
| Target | SMO |
| Pathway | Hedgehog |
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