Identification of a novel extracellular inhibitor of FGF2/FGFR signaling axis by combined virtual screening and NMR spectroscopy approach

Pagano, Katiuscia; Listro, Roberta; Linciano, Pasquale; Rossi, Daniela; Longhi, Elisa; Taraboletti, Giulia; Molinari, Henríette; Collina, Simona; Ragona, Laura

doi:10.1016/j.bioorg.2023.106529

Cited by 4 publications

(4 citation statements)

References 53 publications

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“…After computational analysis, nine main chemical clusters were identified within the library, and the representative general chemical structure was subjected to virtual screening. More information is available in the paper by Pagano et al (2023). The SAFAN results highlighted that (R)-ASME, belonging to MCLib-2022, is a potential binder of HuD.…”

Section: Mclib-2022 Virtual Screeningmentioning

confidence: 99%

“…The output of the analysis is a list of potential targets, ranked in decreasing order (Supplementary Material). The compounds screened to identify new HuD binders belong to an in-house library (MCLib-2022) (Pagano et al, 2023). This library accounts for ca.…”

Section: Mclib-2022 Virtual Screeningmentioning

confidence: 99%

“…Such a collection, which includes both synthetic molecules and secondary metabolites, has been digitized to speed up the drug discovery process. Collected compounds are characterized by significant structural diversity, lead-likeness, and an overall solubility profile to ensure that the resulting hits are worthy of investigation (MedChem Lab, MCL, Department of Drug Sciences, University of Pavia, Pavia, Italy) (Listro et al, 2023;Pagano et al, 2023). Particularly, we focused on two targets, the RNAbinding protein named HuD and the proteasome system since proteasome activators are potentially able to counteract aggregations of dysregulated proteins (Leestemaker et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Neurodegeneration: can metabolites from Eremurus persicus help?

Cavalloro,

Marchesi,

Linciano

et al. 2024

Front. Pharmacol.

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The number of patients affected by neurodegenerative diseases is increasing worldwide, and no effective treatments have been developed yet. Although precision medicine could represent a powerful tool, it remains a challenge due to the high variability among patients. To identify molecules acting with innovative mechanisms of action, we performed a computational investigation using SAFAN technology, focusing specifically on HuD. This target belongs to the human embryonic lethal abnormal visual-like (ELAV) proteins and plays a key role in neuronal plasticity and differentiation. The results highlighted that the molecule able to bind the selected target was (R)-aloesaponol-III-8-methyl ether [(R)-ASME], a metabolite extracted from Eremurus persicus. Notably, this molecule is a TNF-α inhibitor, a cytokine involved in neuroinflammation. To obtain a suitable amount of (R)-ASME to confirm its activity on HuD, we optimized the extraction procedure. Together with ASME, another related metabolite, germichrysone, was isolated. Both ASME and germichrysone underwent biological investigation, but only ASME confirmed its ability to bind HuD. Given the multifactorial nature of neurodegenerative diseases, we decided to investigate ASME as a proteasome activator, being molecules endowed with this kind of activity potentially able to counteract aggregations of dysregulated proteins. ASME was able to activate the considered target both in enzymatic and cellular assays. Therefore, ASME may be considered a promising hit in the fight against neurodegenerative diseases.

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Section: Mclib-2022 Virtual Screeningmentioning

confidence: 99%

Section: Mclib-2022 Virtual Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neurodegeneration: can metabolites from Eremurus persicus help?

Cavalloro,

Marchesi,

Linciano

et al. 2024

Front. Pharmacol.

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“…The targeted approach enhances cancer treatment efficacy by delivering therapeutic agents directly to tumor sites through passive targeting, enhancing permeability and retention effects in nanostructures [14,15], micelles [16,17], liposomes [17][18][19], and nanoemulsions [20]. Additionally, FGF2/FGFR signaling changes are prevalent in various tumor types, with FGF2 being overexpressed in advanced malignant tumors, FGFR2 inhibitors playing a crucial role in tumor growth and progression, and overcoming anticancer drug resistance through novel extracellular inhibitors [21].…”

Section: Introductionmentioning

confidence: 99%

Chemotherapeutic Activity of Imidazolium-Supported Pd(II) o-Vanillylidene Diaminocyclohexane Complexes Immobilized in Nanolipid as Inhibitors for HER2/neu and FGFR2/FGF2 Axis Overexpression in Breast Cancer Cells

Awaji,

Rizk,

Alsaiari

et al. 2023

Pharmaceuticals

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Two bis-(imidazolium–vanillylidene)-(R,R)-diaminocyclohexane ligands (H2(VAN)2dach, H2L1,2) and their Pd(II) complexes (PdL1 and PdL2) were successfully synthesized and structurally characterized using microanalytical and spectral methods. Subsequently, to target the development of new effective and safe anti-breast cancer chemotherapeutic agents, these complexes were encapsulated by lipid nanoparticles (LNPs) to formulate (PdL1LNP and PdL2LNP), which are physicochemically and morphologically characterized. PdL1LNP and PdL2LNP significantly cause DNA fragmentation in MCF-7 cells, while trastuzumab has a 10% damaging activity. Additionally, the encapsulated Pd1,2LNPs complexes activated the apoptotic mechanisms through the upregulated P53 with p < 0.001 and p < 0.05, respectively. The apoptotic activity may be triggered through the activity mechanism of the Pd1,2LNPs in the inhibitory actions against the FGFR2/FGF2 axis on the gene level with p < 0.001 and the Her2/neu with p < 0.05 and p < 0.01. All these aspects have triggered the activity of the PdL1LNP and PdL2LNP to downregulate TGFβ1 by p < 0.01 for both complexes. In conclusion, LNP-encapsulated Pd(II) complexes can be employed as anti-cancer drugs with additional benefits in regulating the signal mechanisms of the apoptotic mechanisms among breast cancer cells with chemotherapeutic-safe actions.

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Synthesis of new phenothiazine derivatives: Molecular docking, assessment of cytotoxic activity and oxidant–antioxidant properties on PCS‐201‐012, HT‐29, and SH‐SY5Y cell lines

Tan,

Kartal,

Yesilyurt

et al. 2024

Archiv der Pharmazie

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Phenothiazine (PTZ) derivatives have been acknowledged as versatile compounds with significant implications across various areas of medicine, particularly, in cancer research. The cytotoxic effects of synthesized compounds on both normal and cancerous cells, along with their oxidant–antioxidant properties, are pivotal factors in cancer treatment strategies. In the current study, eight new PTZ derivatives were synthesized and the compounds' cytotoxic activities were assessed by 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide (MTT) assay while the oxidant–antioxidant properties were evaluated by oxidative stress index (OSI) calculation in SH‐SY5Y (a human neuroblastoma cell line), HT‐29 (a human colorectal adenocarcinoma cell line), and PCS‐201‐012 (a human primary dermal fibroblast cell line) cells. Consequently, the half‐maximal inhibitory concentration (IC50) values of compound 3a were determined to be 218.72, 202.85, and 227.86 μM while the IC50 values of compound 3b were defined to be 227.42, 199.27, and 250.11 μM in PCS‐201‐012, HT‐29, and SH‐SY5Y cells, respectively. Additionally, it was determined that the synthesized compounds demonstrated the lowest OSI in PCS‐201‐012 cells as compared to the other cell lines.

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Identification of a novel extracellular inhibitor of FGF2/FGFR signaling axis by combined virtual screening and NMR spectroscopy approach

Cited by 4 publications

References 53 publications

Neurodegeneration: can metabolites from Eremurus persicus help?

Neurodegeneration: can metabolites from Eremurus persicus help?

Chemotherapeutic Activity of Imidazolium-Supported Pd(II) o-Vanillylidene Diaminocyclohexane Complexes Immobilized in Nanolipid as Inhibitors for HER2/neu and FGFR2/FGF2 Axis Overexpression in Breast Cancer Cells

Synthesis of new phenothiazine derivatives: Molecular docking, assessment of cytotoxic activity and oxidant–antioxidant properties on PCS‐201‐012, HT‐29, and SH‐SY5Y cell lines

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