SAG

Hedgehog pathway activator; Activates Smoothened (SMO)

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Hedgehog pathway activator; Activates Smoothened (SMO)
From: 161 USD

Overview

SAG (Smoothened Agonist) is a chlorobenzothiophene-containing compound which acts as an activator of the G protein-coupled receptor Smoothened (SMO, EC₅₀ = 3 nM; Chen et al.) SMO is a component of the Hedgehog signaling pathway, which is translocated to the primary cilium after stimulation of the Patched receptor by Hedgehog family ligands, leading to pathway activation. SAG activates SMO via direct binding to the heptahelical bundle (Kd = 59 nM), stabilizing a specific conformation of SMO in cilia and leading to increased downstream gene expression (Rohatgi et al.). SAG abrogates cyclopamine inhibition of SMO, indicating that it acts downstream of cyclopamine (Frank-Kamenetsky et al.; Chen et al.; Lewis & Krieg).

DIFFERENTIATION
· Improves neuronal differentiation of human induced pluripotent stem cells (Mak et al.).

MAINTENANCE
· Induces proliferation and survival of neuronal and glial precursors in vitro and in vivo (Bragina et al.).
· Prevents glucocorticoid neurotoxicity in Math1-Cre, SmoM2 transgenic mice (Heine et al.).
· Rescues cerebellar size and behavioral phenotypes in the Ts65Dn mouse model of Down Syndrome (Das et al.).
Alternative Names:
Smoothened Agonist
CAS Number:
912545-86-9
Chemical Formula:
C₂₈H₂₈ClN₃OS
Molecular Weight:
490.1 g/mol
Purity:
≥ 98%
Pathway:
Hedgehog
Target:
SMO

Scientific Resources

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(4)

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Data and Publications

Publications

(8)
Methods (San Diego, Calif.) 2014 APR

Reagents for developmental regulation of Hedgehog signaling.

Lewis C and Krieg PA

Abstract

We have examined a number of reagents for their ability to modulate activity of the Hh signaling pathway during embryonic development of Xenopus. In particular we have focused on regulation of events occurring during tailbud stages and later. Two inducible protein reagents based on the Gli1 and Gli3 transcription factors were generated and the activity of these proteins was compared to the Hh signaling pathway inhibitor, cyclopamine, and the activators, Smoothened agonist (SAG) and purmorphamine (PMA). Effectiveness of reagents was assayed using both molecular biological techniques and biological readouts. We found that the small molecule modulators of the Hh pathway were highly specific and effective and produced results generally superior to the more conventional protein reagents for examination of later stage developmental processes.
Science translational medicine 2013 SEP

Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model.

Das I et al.

Abstract

Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus. We show that a single treatment of newborn mice with the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults. Further, SAG treatment at birth rescued phenotypes associated with hippocampal deficits that occur in untreated adult Ts65Dn mice. This treatment resulted in behavioral improvements and normalized performance in the Morris water maze task for learning and memory. SAG treatment also produced physiological effects and partially rescued both N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity and NMDA/AMPA receptor ratio, physiological measures associated with memory. These outcomes confirm an important role for the hedgehog pathway in cerebellar development and raise the possibility for its direct influence in hippocampal function. The positive results from this approach suggest a possible direction for therapeutic intervention to improve cognitive function for this population.
Stem cells international 2012 JAN

Small molecules greatly improve conversion of human-induced pluripotent stem cells to the neuronal lineage.

Mak SK et al.

Abstract

Efficient in vitro differentiation into specific cell types is more important than ever after the breakthrough in nuclear reprogramming of somatic cells and its potential for disease modeling and drug screening. Key success factors for neuronal differentiation are the yield of desired neuronal marker expression, reproducibility, length, and cost. Three main neuronal differentiation approaches are stromal-induced neuronal differentiation, embryoid body (EB) differentiation, and direct neuronal differentiation. Here, we describe our neurodifferentiation protocol using small molecules that very efficiently promote neural induction in a 5-stage EB protocol from six induced pluripotent stem cells (iPSC) lines from patients with Parkinson's disease and controls. This protocol generates neural precursors using Dorsomorphin and SB431542 and further maturation into dopaminergic neurons by replacing sonic hedgehog with purmorphamine or smoothened agonist. The advantage of this approach is that all patient-specific iPSC lines tested in this study were successfully and consistently coaxed into the neural lineage.
Science Translational Medicine 2011

A Small-Molecule Smoothened Agonist Prevents Glucocorticoid-Induced Neonatal Cerebellar Injury

Heine VM et al.

Abstract

Glucocorticoids are used for treating preterm neonatal infants suffering from life-threatening lung, airway, and cardiovascular conditions. However, several studies have raised concerns about detrimental effects of postnatal glucocorticoid administration on the developing brain leading to cognitive impairment, cerebral palsy, and hypoplasia of the cerebellum, a brain region critical for coordination of movement and higher-order neurological functions. Previously, we showed that glucocorticoids inhibit Sonic hedgehog-Smoothened (Shh-Smo) signaling, the major mitogenic pathway for cerebellar granule neuron precursors. Conversely, activation of Shh-Smo in transgenic mice protects against glucocorticoid-induced neurotoxic effects through induction of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) pathway. Here, we show that systemic administration of a small-molecule agonist of the Shh-Smo pathway (SAG) prevented the neurotoxic effects of glucocorticoids. SAG did not interfere with the beneficial effects of glucocorticoids on lung maturation, and despite the known associations of the Shh pathway with neoplasia, we found that transient (1-week-long) SAG treatment of neonatal animals was well tolerated and did not promote tumor formation. These findings suggest that a small-molecule agonist of Smo has potential as a neuroprotective agent in neonates at risk for glucocorticoid-induced neonatal cerebellar injury.
Neuroscience letters 2010

Smoothened agonist augments proliferation and survival of neural cells.

Bragina O et al.

Abstract

Sonic hedgehog signaling pathway is important in developmental processes like dorsoventral neural tube patterning, neural stem cell proliferation and neuronal and glial cell survival. Shh is also implicated in the regulation of the adult hippocampal neurogenesis. Recently, nonpeptidyl Smoothened activators of the Shh pathway have been identified. The aim of this study was to investigate the effects of chlorobenzothiophene-containing molecule, Smo agonist (SAG), which has been shown to activate Shh signaling pathway, in neurogenesis and neuronal survival in in vitro and in vivo models. Our in vitro experiments showed that SAG induces increased expression of Gli1 mRNA, transcriptional target and mediator of Shh signal. In vitro experiments also demonstrated that SAG in low-nanomolar concentrations induces proliferation of neuronal and glial precursors without affecting the differentiation pattern of newly produced cells. In contrast to Shh, SAG did not induce neurotoxicity in neuronal cultures. The SAG and Shh treatment also promoted the survival of newly generated neural cells in the dentate gyrus after their intracerebroventricular administration to adult rats. We propose that SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial.
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