Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine

Wang, Jiangbo; Lü, Jiuyi; Bond, Michael C.; Chen, Minyong; Ren, Xiu-Rong; Lyerly, H. Kim; Barak, Larry S.; Chen, Wei

doi:10.1073/pnas.0910712107

Cited by 78 publications

(102 citation statements)

References 29 publications

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“…Consequently, GSA-10 mechanism of action differs from that of selected glucocorticoids proposed to bind Smo, to activate Gli, and to promote mouse GCP proliferation (Wang et al, 2010). Numerous other physiologic roles are associated with Hh signaling and, potentially, with Smo modulation in the developing or adult brain.…”

Section: Discussionmentioning

confidence: 99%

“…SAG and purmorphamine have been used for modulating various patterning events in embryonic stem cells and adult neural precursor cells (FrankKamenetsky et al, 2002;Danjo et al, 2011). Further investigations are necessary for delineating the potential interest of several glucocorticoids (Wang et al, 2010) and oxysterols (Corcoran and Scott, 2006;Nachtergaele et al, 2012) as Smo agonists. However, only a limited number of Smo agonists have yet been characterized, and none has reached clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

et al. 2013

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Activation of the Smoothened (Smo) receptor mediates Hedgehog (Hh) signaling. Hh inhibitors are in clinical trials for cancer, and small-molecule Smo agonists may have therapeutic interests in regenerative medicine. Here, we have generated and validated a pharmacophoric model for Smo agonists and used this model for the virtual screening of a library of commercially available compounds. Among the 20 top-scoring ligands, we have identified and characterized a novel quinolinecarboxamide derivative, propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate, (GSA-10), as a Smo agonist. GSA-10 fits to the agonist pharmacophoric model with two hydrogen bond acceptor groups and four hydrophobic regions. Using pharmacological, biochemical, and molecular approaches, we provide compelling evidence that GSA-10 acts at Smo to promote the differentiation of multipotent mesenchymal progenitor cells into osteoblasts. However, this molecule does not display the hallmarks of reference Smo agonists. Remarkably, GSA-10 does not recognize the classic bodipy-cyclopamine binding site. Its effect on cell differentiation is inhibited by Smo antagonists, such as MRT-83, SANT-1, LDE225, and M25 in the nanomolar range, by GDC-0449 in the micromolar range, but not by cyclopamine and CUR61414. Thus, GSA-10 allows the pharmacological characterization of a novel Smo active site, which is notably not targeted to the primary cilium and strongly potentiated by forskolin and cholera toxin. GSA-10 belongs to a new class of Smo agonists and will be helpful for dissecting Hh mechanism of action, with important implications in physiology and in therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

et al. 2013

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“…Hedgehog activators are prime candidates for therapeutics to initiate or modulate tissue selfrepair [149]. Fig.…”

Section: Stem Cell Therapymentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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“…1 The findings suggest that glucocorticoids-and their potential derivativescould be repurposed for various tissue repair and regenerative medicine applications.…”

mentioning

confidence: 99%

Glucocorticoids get Smoothened

Lou¹

2010

Science-Business eXchange

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Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine

Abstract: Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation.

Cited by 78 publications

References 29 publications

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Glucocorticoids get Smoothened

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