Mining Natural Compounds to Target WNT Signaling: Land and Sea Tales

Katanaev, Vladimir L.; Blagodatski, Artem; Xu, Jiabin; Koval, Alexey

doi:10.1007/164_2021_530

Cited by 10 publications

(10 citation statements)

References 113 publications

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“…In context of these findings and inspired by our recent success on the subject, such as repositioning of the lichen-sourced compound clofazimine and its derivatives against Wnt signaling ( Xu et al, 2020 ; Koval et al, 2021 ) we have embarked on a discovery of the novel anti-Wnt therapies using our platform for targeted screening of the such compounds ( Shaw et al, 2019 ; Katanaev et al, 2021 ). Since there are multiple attractive targets within pathway which might mediate pharmacologically relevant anti-cancer effect, we have created a high-throughput system based on the triple-negative breast cancer cells stably transfected with TopFlash reporter, thus accurately representing the entire repertoire of pathway aberrations driving the disease ( Veeman et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

et al. 2022

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The Wnt signaling pathway controls multiple events during embryonic development of multicellular animals and is carcinogenic when aberrantly activated in adults. Breast cancer and triple-negative breast cancer (TNBC) in particular depend upon Wnt pathway overactivation. Despite this importance, no Wnt pathway-targeting drugs are currently available, which necessitates novel approaches to search for therapeutically relevant compounds targeting this oncogenic pathway. Stilbene analogs represent an under-explored field of therapeutic natural products research. In the present work, a library of complex stilbene derivatives was obtained through biotransformation of a mixture of resveratrol and pterostilbene using the enzymatic secretome of Botrytis cinerea. To improve the chemodiversity, the reactions were performed using i-PrOH, n-BuOH, i-BuOH, EtOH, or MeOH as cosolvents. Using this strategy, a series of 73 unusual derivatives was generated distributed among 6 scaffolds; 55 derivatives represent novel compounds. The structure of each compound isolated was determined by nuclear magnetic resonance and high-resolution mass spectrometry. The inhibitory activity of the isolated compounds against the oncogenic Wnt pathway was comprehensively quantified and correlated with their capacity to inhibit the growth of the cancer cells, leading to insights into structure-activity relationships of the derivatives. Finally, we have dissected mechanistic details of the stilbene derivatives activity within the pathway.

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Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

et al. 2022

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“…Natural products have always been one of the major sources of new drugs, including oncology therapeutics [ 5 , 6 , 7 ]. Porphyrin-type compounds such as chlorins can act as efficient photosensitizers and have been found in diverse living groups [ 4 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Chlorin Endogenous to the North Pacific Brittle Star Ophiura sarsii for Photodynamic Therapy Applications in Breast Cancer and Glioblastoma Models

et al. 2022

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Photodynamic therapy (PDT) represents a powerful avenue for anticancer treatment. PDT relies on the use of photosensitizers—compounds accumulating in the tumor and converted from benign to cytotoxic upon targeted photoactivation. We here describe (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (ETPA) as a major metabolite of the North Pacific brittle stars Ophiura sarsii. As a chlorin, ETPA efficiently produces singlet oxygen upon red-light photoactivation and exerts powerful sub-micromolar phototoxicity against a panel of cancer cell lines in vitro. In a mouse model of glioblastoma, intravenous ETPA injection combined with targeted red laser irradiation induced strong necrotic ablation of the brain tumor. Along with the straightforward ETPA purification protocol and abundance of O. sarsii, these studies pave the way for the development of ETPA as a novel natural product-based photodynamic therapeutic.

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“…Our research has been aimed at discovering novel Wnt-pathway inhibitors ( Koval and Katanaev, 2012 ; Katanaev et al, 2021 ; Larasati et al, 2022 ). We have previously developed a High-Throughput Screening (HTS) assay based on a triple-negative breast cancer (TNBC) cell line BT-20 that could be adapted to any β-catenin-dependent cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

Boudou

Mattio²,

Koval³

et al. 2022

Front. Pharmacol.

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The Wnt-pathway has a critical role in development and tissue homeostasis and has attracted increased attention to develop anticancer drugs due to its aberrant activation in many cancers. In this study, we identified a novel small molecule series with a thienopyrimidine scaffold acting as a downstream inhibitor of the β-catenin-dependent Wnt-pathway. This novel chemotype was investigated using Wnt-dependent triple-negative breast cancer (TNBC) cell lines. Structure activity relationship (SAR) exploration led to identification of low micromolar compounds such as 5a, 5d, 5e and a novel series with quinazoline scaffold such as 9d. Further investigation showed translation of activity to inhibit cancer survival of HCC1395 and MDA-MB-468 TNBC cell lines without affecting a non-cancerous breast epithelial cell line MCF10a. This anti-proliferative effect was synergistic to docetaxel treatment. Collectively, we identified novel chemotypes acting as a downstream inhibitor of β-catenin-dependent Wnt-pathway that could expand therapeutic options to manage TNBC.

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Mining Natural Compounds to Target WNT Signaling: Land and Sea Tales

Cited by 10 publications

References 113 publications

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

Chlorin Endogenous to the North Pacific Brittle Star Ophiura sarsii for Photodynamic Therapy Applications in Breast Cancer and Glioblastoma Models

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

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