Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway

DeBerardinis, Albert M.; Banerjee, Upasana; Miller, Michele; Lemieux, Steven; Hadden, M. Kyle

doi:10.1016/j.bmcl.2012.05.037

Cited by 19 publications

(17 citation statements)

References 16 publications

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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).…”

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confidence: 93%

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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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confidence: 93%

“…11 In addition, 4 did not bind to purified VDR nor did it activate VDR signaling in cell culture. On the basis of these results, and the fact that 4 is readily available from VD3 in a one pot, two-step reaction sequence, we sought to use this compound as a basis for the development of improved VD3-based Hh pathway inhibitors.…”

mentioning

confidence: 95%

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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“…Nonetheless, vitamin D3 is a potent inhibitor of the Hh pathway downstream of Patched-1 and has been used to reduce proliferation of Hh-dependent cancers [45][46][47]. Importantly, the structural requirements of vitamin D3 for Hh pathway inhibition are distinct than those required for activation of the vitamin D receptor (VDR), suggesting that vitamin D3 may target a component of the Hh pathway [48].…”

Section: Regulation Of Vitamin D Metabolitesmentioning

confidence: 99%

Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

Riobó

2014

Topics in Medicinal Chemistry

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The Hedgehog (Hh) signaling pathway has received a great deal of attention in the past decade due to its involvement in cancer, angiogenesis, and fibrosis. Several inhibitors of the pathway were developed which target the 7-transmembrane protein Smoothened (Smo), core component of the canonical pathway that controls Gli-dependent transcriptional activity. However, recent studies revealed that the Hh pathway has other transcription-independent functions, collectively known as "non-canonical signaling." This review describes the role and function of each Hh pathway component in canonical and non-canonical signaling, with emphasis on the role of Smo as a GPCR that selectively activates heterotrimeric G i proteins.

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“…To facilitate clinical application, avoiding the side effects that cause prolonged administration of vitamin D3, researchers have recently produced semisynthetic derivatives that retain the ability to repress Hh and do not bind to VDR, which may be tested in future preclinical and clinical trials. 99 …”

Section: Vitamin D3 (Calcitriol)mentioning

confidence: 99%

Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

Cucchi¹,

Occhione²,

Gulino³

et al. 2012

JEP

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Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified – from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib – most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.

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Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway

Cited by 19 publications

References 16 publications

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

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

Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

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