Potent small molecule Hedgehog agonists induce VEGF expression in vitro

Seifert, Katrin; Büttner, Anita; Rigol, Stephan; Eilert, Nicole; Wandel, Elke; Giannis, Athanassios

doi:10.1016/j.bmc.2012.08.026

Cited by 24 publications

(12 citation statements)

References 34 publications

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“…Reductive amination of 14 with benzylamine furnished the secondary amine 15 42 . 15 was then either coupled directly with isocyanates or with anilines using cabonyldiimidazole (CDI) as a coupling agent ( 21 – 46 , Tables 2 & 3) 54–57 . Given the wider availability of anilines, we used the CDI-mediated reaction for our parallel chemistry.…”

Section: Resultsmentioning

confidence: 99%

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

et al. 2018

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We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CL = 170 mL/min/kg). This work lays out the discovery of an orally bioavailable analogue, NAcM-OPT (67). Compound 67 retains the favorable biochemical and cellular activity of compound 7 but is significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently used to study the effects of acute pharmacologic inhibition of the DCN1-UBE2M interaction on the NEDD8/CUL pathway.

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Section: Resultsmentioning

confidence: 99%

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

et al. 2018

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“…The cytotoxicity of costic acid was investigated in human umbilical vein endothelial (HUVE) cells (PromoCell) by incubation with the cell proliferation reagent WST-1 (Roche, Mannheim, Germany) as previously described [53]. Briefly, 7500 cells per well (Greiner Bio-one, 96 well microplate, white, μclear bottom) were exposed to different compound concentrations (100 μL/well, containing less than 0.5% DMSO (v/v)) for 24 h before adding the WST-1 reagent.…”

Section: Methodsmentioning

confidence: 99%

Use of costic acid, a natural extract from Dittrichia viscosa, for the control of Varroa destructor, a parasite of the European honey bee

Sofou

Isaakidis

Spyros

et al. 2017

Beilstein J. Org. Chem.

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Costic acid has been isolated from the plant Dittrichia viscosa and its efficacy against Varroa destructor, a parasite of Apis mellifera, the European honey bee, has been studied. Costic acid exhibited potent in vivo acaricidal activity against the parasite. Initial experiments showed that the compound is not toxic for human umbilical vein endothelial cells (HUVEC) at concentrations of up to 230 micromolar (μM), indicating that costic acid could be used as a safe, low-cost and efficient agent for controlling varroosis in honey bee colonies.

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“…Since these initial studies, two detailed SAR reports in the scientific literature have provided insight into the design and structural requirements for pathway activation for this class of Hh pathway agonists 74. 75 First, for the central 1,4‐diaminocyclohexane moiety the trans orientation was critical for activity, and while the addition of a singular methyl group to the 4‐position amine enhanced activity approximately 125‐fold, larger substituents completely abolished activity 74. SAR for the 3‐chlorobenzothiophene group demonstrated that replacement of the chlorine with a methyl was tolerated; however, substitution with a hydrogen resulted in a complete loss of activity.…”

Section: Small‐molecule Hh Pathway Agonistsmentioning

confidence: 99%

Hedgehog Pathway Agonism: Therapeutic Potential and Small‐Molecule Development

Hadden¹

2013

ChemMedChem

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The Hedgehog (Hh) pathway is a developmental signaling pathway that plays multiple roles during embryonic development and in adult tissues. Constitutive Hh signaling has been linked to the development and progression of several forms of cancer, and the application of small-molecule pathway inhibitors as anticancer chemotherapeutics is well studied and clearly defined. Activation of the Hh pathway as a therapeutic strategy for a variety of degenerative or ischemic disorders has also been proposed; however, the development of small-molecule Hh agonists has received less attention. The goal of this review is to highlight the recent evidence supporting the therapeutic potential of Hh pathway activators and to provide a comprehensive overview of small-molecule pathway agonists.

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Potent small molecule Hedgehog agonists induce VEGF expression in vitro

Cited by 24 publications

References 34 publications

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

Use of costic acid, a natural extract from Dittrichia viscosa, for the control of Varroa destructor, a parasite of the European honey bee

Hedgehog Pathway Agonism: Therapeutic Potential and Small‐Molecule Development

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