Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors

Banerjee, Upasana; Ghosh, Monisha; Hadden, M. Kyle

doi:10.1016/j.bmcl.2011.12.081

Cited by 17 publications

(25 citation statements)

References 23 publications

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“…In this well-studied model system for evaluating small molecule inhibition of Hh signaling, addition of an exogenous Hh agonist (recombinant Hh ligand or small molecule) results in a characteristic increase in Gli1 mRNA expression. 28 Concomitant incubation with a pathway inhibitor reduces Gli1 expression. Analogues that reduced Gli1 mRNA levels below 20% in this assay were subsequently evaluated for their ability to reduce Gli1 mRNA expression levels in a concentration-dependent fashion in these cells and the Hh-dependent murine BCC cell line ASZ.…”

Section: Resultsmentioning

confidence: 99%

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

et al. 2016

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Itraconazole (ITZ) is an FDA-approved member of the triazole class of anti-fungal agents. Two recent drug repurposing screens identified ITZ as a promising anti-cancer chemotherapeutic that inhibits both angiogenesis and the hedgehog (Hh) signaling pathway. We have synthesized and evaluated first and second generation ITZ analogues for their anti-Hh and anti-angiogenic activities to more fully probe the structural requirements for these anti-cancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis, but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anti-cancer properties of the ITZ scaffold.

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Section: Resultsmentioning

confidence: 99%

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

et al. 2016

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“…10,11 In addition, we have previously demonstrated that this cell line responds to VDR activation 10,11 with significant up-regulation of Cyp24A1, a well-characterized target gene of canonical vitamin D signaling. 16 For this assay, The results of this initial study provided important preliminary SAR for the ability of this class of VD3-based analogues to selectively inhibit Hh pathway signaling (Table 1).…”

mentioning

confidence: 91%

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

DeBerardinis

Banerjee

Hadden

2013

ACS Med. Chem. Lett.

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Previous structure−activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these compounds in a series of cellular assays demonstrated their ability to potently and selectively downregulate Hh pathway signaling. The most active of these, 17, inhibited pathway signaling in Hh-dependent mouse fibroblasts (IC 50 = 0.74 ± 0.1 μM) and cultured cancer cells (IC 50 values 3.8 ± 0.1 to 5.2 ± 0.2 μM). In addition, 17 demonstrated reduced activation of the vitamin D receptor (VDR) compared to VD3 in these cellular models. These results suggest that VD3-based analogues with an aromatic A-ring are a valid scaffold for the development of more selective and potent Hh pathway inhibitors and identify 17 as an intriguing lead from this class of compounds for further development. In addition, our analysis of Hh pathway inhibitors in cancer cells suggests that the murine basal cell carcinoma cell line ASZ001 and the human medulloblastoma cell line DAOY are appropriate in vitro cancer models for early stage evaluation of pathway inhibition.

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“…General protocols for cell culture, qPCR, and Hh inhibition in C3H10T1/2 and ASZ001 cells are as previously described . Data were analyzed with GraphPad Prism 5 and reported values represent the mean±SEM for at least two separate experiments carried out in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…The seco ‐steroid vitamin D3 (VD3, 1 ) has been recognized as a moderate Hh pathway inhibitor in recent years . Initial structure–activity relationship (SAR) studies on this scaffold led to the identification of Grundmann's alcohol (GA, 2 ), also termed the “northern region” of VD3, as the pharmacophore responsible for VD3‐mediated Hh pathway inhibition .…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors

Wen

Hadden

2018

ChemMedChem

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The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small-molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the "northern region" of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C4 hydroxy group and C3α proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 ((1R,3aR,4R,7aR)-1-[(R)-1,5-dimethylhexyl]-4-(4-aminophenoxy)-7a-methyloctahydro-1H-indene) demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway.

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Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors

Cited by 17 publications

References 23 publications

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors

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