scholarly journals Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 589 ◽  
Author(s):  
Artem Blagodatski ◽  
Antonina Klimenko ◽  
Lee Jia ◽  
Vladimir L. Katanaev
Keyword(s):  
Natural Products ◽  
Wnt Signaling ◽  
Small Molecule ◽  
Wnt Pathway ◽  
Therapeutic Potential ◽  
Biologically Active ◽  
Bioactive Molecules ◽  
Small Molecule Modulators ◽  
Multicellular Organisms ◽  
Important Therapeutic Target

The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.

Natural products targeting cancer stem cells: a revisit

2021 ◽  
Vol 28 ◽  
Author(s):  
Jiahua Cui ◽  
Jiajun Qian ◽  
Larry Ming-Cheung Chow ◽  
Jinping Jia
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Biologically Active ◽  
Cellular Targets ◽  
Drug Candidates ◽  
Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

scholarly journals CancerGram: An Effective Classifier for Differentiating Anticancer from Antimicrobial Peptides

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1045
Author(s):  
Michał Burdukiewicz ◽  
Katarzyna Sidorczuk ◽  
Dominik Rafacz ◽  
Filip Pietluch ◽  
Mateusz Bąkała ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Cancer Cells ◽  
Plasma Membranes ◽  
Therapeutic Potential ◽  
Kappa Statistic ◽  
R Package ◽  
Bioactive Molecules ◽  
Membrane Composition ◽  
Anticancer Peptides ◽  
Multicellular Organisms

Antimicrobial peptides (AMPs) constitute a diverse group of bioactive molecules that provide multicellular organisms with protection against microorganisms, and microorganisms with weaponry for competition. Some AMPs can target cancer cells; thus, they are called anticancer peptides (ACPs). Due to their small size, positive charge, hydrophobicity and amphipathicity, AMPs and ACPs interact with negatively charged components of biological membranes. AMPs preferentially permeabilize microbial membranes, but ACPs additionally target mitochondrial and plasma membranes of cancer cells. The preference towards mitochondrial membranes is explained by their membrane potential, membrane composition resulting from α-proteobacterial origin and the fact that mitochondrial targeting signals could have evolved from AMPs. Taking into account the therapeutic potential of ACPs and millions of deaths due to cancer annually, it is of vital importance to find new cationic peptides that selectively destroy cancer cells. Therefore, to reduce the costs of experimental research, we have created a robust computational tool, CancerGram, that uses n-grams and random forests for predicting ACPs. Compared to other ACP classifiers, CancerGram is the first three-class model that effectively classifies peptides into: ACPs, AMPs and non-ACPs/non-AMPs, with AU1U amounting to 0.89 and a Kappa statistic of 0.65. CancerGram is available as a web server and R package on GitHub.

Inhibition Of Wnt Signaling In Chronic Lymphocytic Leukemia Has Synergistic Cytotoxicity With Ibrutinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5306-5306
Author(s):  
Christina C.N. Wu ◽  
Michael Y. Choi ◽  
Fitzgerald Lao ◽  
Thomas J. Kipps ◽  
Dennis A. Carson
Keyword(s):  
Wnt Signaling ◽  
Board Of Directors ◽  
Small Molecule ◽  
Wnt Pathway ◽  
Stem Cell Marker ◽  
Synergistic Activity ◽  
Advisory Committees ◽  
Prognostic Features ◽  
Synergistic Cytotoxicity ◽  
Wnt Inhibitors

Abstract The Wnt pathway plays a major role in early embryonic development and in various cancers. We found that CLL cells have activated Wnt-signaling (Proc Natl Acad SciUSA 2004, PMID: 14973184) and express genes commonly associated with B-cell progenitors or stem cells, especially the Wnt factor-related genes such as LEF1, Wnt16, and Frizzled3 (FZD3). Also, compared to normal B lymphocytes, CLL cells express high levels of the putative cancer stem cell marker Aldehyde Dehydrogenase (ALDH), especially those CLL cells with high-risk prognostic features (Leuk and Lymph, 2013, PMID 22784365) and are highly sensitive to inhibitors of Wnt signaling (Proc Natl Acad SciUSA 2004, PMID: 3156152). Finally, next generation DNA sequencing studies have identified mutations in 12 different Wnt pathway genes in 15-20% of CLL patients. Collectively, the results of these studies imply that Wnt-signaling may be an excellent target for developing effective novel therapies for patients with CLL (Oncotarget 2011, PMID: 21860066). We compared different classes of Wnt inhibitors identified by screening of natural compound and small molecule libraries for cytotoxicity in primary leukemic cells from patients with CLL. Among all the Wnt inhibitors tested, Salinomycin and Agelastatin (naturally occurring compounds targeting LRP5/6 degradation or LEF1 down-regulation as previously reported by our groups) consistently showed dose dependent cytotoxicity at concentrations lower than 1 µM. In contrast, small molecule Wnt inhibitors targeting more proximal elements of the Wnt pathway, porcupine (Wnt-C59) and tankyrase, (XAV-939) had little direct effect on in vitro CLL cell viability even at 10 µM. The Wnt inhibitors were also utilized as tool compounds to evaluate the effect of combined inhibition of the Wnt pathway and other pathways. Interestingly, we identified synergistic activity between Wnt inhibitors and other inhibitors, including Ibrutinib and Idelalisib. By colorimetric and flow cytometry assays, we demonstrated that significant cell death was induced with combinations of the agents at concentrations at which little or no cytotoxicity was seen with either agent alone. The studies further demonstrate that the Wnt pathway is a viable target for the treatment of CLL and may potentiate other emerging CLL therapies. Disclosures: Kipps: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Speakers Bureau; Abbvie: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals A Review of Biologically Active Natural Products from Mediterranean Wild Edible Plants: Benefits in the Treatment of Obesity and Its Related Disorders

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 649 ◽  
Author(s):  
Mariangela Marrelli ◽  
Giancarlo Statti ◽  
Filomena Conforti
Keyword(s):  
Natural Products ◽  
Therapeutic Potential ◽  
Biological Significance ◽  
Biologically Active ◽  
Wild Food ◽  
Wild Foods ◽  
Food And Agriculture ◽  
Edible Species

Wild foods constitute an essential component of people’s diets around the world. According to the Food and Agriculture Organization (FAO), over 100 million people in the EU consume wild foods, while 65 million collect some form of wild food themselves. The Mediterranean basin is a biodiversity hotspot of wild edible species. Nowadays, due to the renewed interest in alimurgic plants and the recent findings on the beneficial role of their phytochemical constituents, these species have been defined as “new functional foods”. Research on natural products has recently regained importance with the growing understanding of their biological significance. Botanical food supplements marketed for weight and fat loss in obese subjects will be one of the most important items in marketed nutraceuticals. The aim of this report was to review the phytochemical compounds of Mediterranean wild edible species and their therapeutic potential against obesity and its related disorders. Results on the in vitro and in vivo activity of the most interesting plant extracts and their bioactive components are presented and discussed. The most interesting discoveries on their mechanisms of action are reported as well. Overall, this contribution highlights the importance and beneficial health roles of wild edible species.

scholarly journals Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach

2010 ◽  
Vol 299 (2) ◽  
pp. G293-G300 ◽  
Author(s):  
Wei Chen ◽  
Minyong Chen ◽  
Larry S. Barak
Keyword(s):  
Colon Cancer ◽  
Drug Discovery ◽  
Wnt Signaling ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Wnt Pathway ◽  
Protein Targets ◽  
Wnt Proteins ◽  
Development And Differentiation

Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory's strategy for identifying novel Wnt signaling antagonists using high-throughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.

scholarly journals Development of a Testing Funnel for Identification of Small-Molecule Modulators Targeting Secretin Receptors

2020 ◽  
Vol 26 (1) ◽  
pp. 1-16
Author(s):  
Daniela G. Dengler ◽  
Qing Sun ◽  
John Holleran ◽  
Sirkku Pollari ◽  
Jannis Beutel ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Peptide Ligand ◽  
Screening Assay ◽  
Obesity And Diabetes ◽  
Secretin Receptor ◽  
Class B ◽  
Combination Of Methods ◽  
Small Molecule Modulators

The secretin receptor (SCTR), a prototypical class B G protein-coupled receptor (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of its endogenous peptide ligand secretin. SCTRs can be found in a variety of tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, and brain. Beyond that, modulation of SCTR-mediated signaling has therapeutic potential for the treatment of multiple diseases, such as heart failure, obesity, and diabetes. However, no ligands other than secretin and its peptide analogs have been described to regulate SCTRs, probably due to inherent challenges in family B GPCR drug discovery. Here we report creation of a testing funnel that allowed targeted detection of SCTR small-molecule activators. Pursuing the strategy to identify positive allosteric modulators (PAMs), we established a unique primary screening assay employing a mixture of three orthosteric stimulators that was compared in a screening campaign testing 12,000 small-molecule compounds. Beyond that, we developed a comprehensive set of secondary assays, such as a radiolabel-free target engagement assay and a NanoBiT (NanoLuc Binary Technology)-based approach to detect β-arrestin-2 recruitment, all feasible in a high-throughput environment as well as capable of profiling ligands and hits regarding their effect on binding and receptor function. This combination of methods enabled the discovery of five promising scaffolds, four of which have been validated and further characterized with respect to their allosteric activities. We propose that our results may serve as starting points for developing the first in vivo active small molecules targeting SCTRs.

A comprehensive review on pyranoindole-containing agents

2021 ◽  
Vol 28 ◽  
Author(s):  
Alessia Catalano ◽  
Domenico Iacopetta ◽  
Jessica Ceramella ◽  
Carmela Saturnino ◽  
Maria Stefania Sinicropi
Keyword(s):  
Natural Products ◽  
Heterocyclic Compounds ◽  
Biological Activities ◽  
Therapeutic Agents ◽  
Biologically Active ◽  
Bioactive Molecules ◽  
Structural Motif ◽  
Huge Number ◽  
Naturally Occurring ◽  
Active Natural

: A huge number of nitrogen-containing heterocyclic compounds are ubiquitous in natural products, pharmaceuticals, and bioactive molecules. Among these, the pyranoindole represents an important structural motif, as it constitutes the central subunit in both the biologically active natural products and therapeutic agents. Talathermophilins, notoamides, norgeamides, carneamides, and versicamides are examples of naturally occurring pyranoindoles, while the well-known etodolac and pemedolac are a tetrahydropyrano[3,4-b]indole deriving from synthetic procedures. Besides the well-known antiinflammatory and fibrinolytic activity, molecules comprising the pyranoindole framework have been demonstrated to exhibit various biological activities, such as antiulcer, antidepressant, analgesic, and antiproliferative. Herein, we report the most common natural and synthetic products bearing a pyranoindole nucleus, their syntheses, and biological activities.

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