A5072879742- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Chemical Synthesis and Analysis
- Protease and Inhibitor Mechanisms
- RNA Interference and Gene Delivery
- Histone Deacetylase Inhibitors Research
- HIV/AIDS drug development and treatment
- Protein Degradation and Inhibitors
- Cancer Mechanisms and Therapy
- Ferrocene Chemistry and Applications
- DNA and Nucleic Acid Chemistry
- Inflammatory mediators and NSAID effects
- Receptor Mechanisms and Signaling
- Advanced biosensing and bioanalysis techniques
- Chemokine receptors and signaling
- RNA Research and Splicing
- Cholinesterase and Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Biochemical and Molecular Research
- Wnt/β-catenin signaling in development and cancer
- Bioactive Compounds and Antitumor Agents
- Synthesis and Reactivity of Heterocycles
- Signaling Pathways in Disease
University of Naples Federico II
2014-2024
University of Siena
2012-2015
Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cells 5-FU. Herein, we developed 16 peptides based on Pep3 (1), only known peptide acting through this mechanism. The new peptides, notably 3 9, showed lower IC50 values than 1. When incorporated into tumor-targeted biodegradable nanoparticles, these...
Abstract In the complex scenario of cancer, treatment with compounds targeting multiple cell pathways has been emerging. Glioblastoma Multiforme (GBM), p53 and Translocator Protein (TSPO), both acting as apoptosis inducers, represent two attractive intracellular targets. On this basis, novel indolylglyoxylyldipeptides, rationally designed to activate TSPO p53, were synthesized biologically characterized. The new able bind reactivate functionality, through dissociation from its physiological...
We developed a new class of covalent inhibitors Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, validated target for the treatment malaria, by screening small library 3-bromo-isoxazoline derivatives that inactivate enzyme through covalent, selective bond to catalytic cysteine, as demonstrated mass spectrometry. Substituents on isoxazolinic ring modulated potency up 20-fold, predominantly due an electrostatic effect, assessed computational analysis.
Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate role these enzymes in physiopathological mechanisms but also lead structures for development further antitumor agents. After application a molecular pruning approach hardly optimizable very cell-permeable garcinol core structure, we prepared many analogues that were screened their inhibitory effects using biochemical biophysical (SPR) assays. Further...
Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on reported connection among histone deacetylases (HDACs) glycogen synthase kinase 3β (GSK-3β), herein we present discovery biochemical characterization first-in-class hit compound able to exert promising anti-AD effects by modulating targeted proteins low micromolar range concentration. Compound 11 induces an increase...
Simulating protein flexibility is a major issue in the docking-based drug-design process for which single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with challenge including receptor plasticity virtual screening campaign aimed at finding β-secretase inhibitors. To this aim, incorporated simulations by using an ensemble static X-ray enzyme structures to screen National Cancer Institute database. A unified description motion was also...
Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of extracellular matrix osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage and halt progression OA. Herein, we report synthesis vitro evaluation new series selective possessing an arylsulfonamidic scaffold. Among these inhibitors, very promising compound was discovered exhibiting nanomolar activity for highly compared MMP-1,...
The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). debate on respective contributions GSK-3α GSK-3β AD pathology AML is ongoing. Thus, identification potent GSK-3α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate effect inhibition in models. analysis all available crystallized GSK-3 structures provided a simplified...
Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations led to identification structural class 18 inhibited with an IC50 0.24 μM and tau phosphorylation in cell-based assay. It proved be selective inhibitor GSK-3 against panel 17 kinases showed >10-fold selectivity CDK2. Calculated physicochemical properties Volsurf predictions suggested that compound has potential diffuse passively across...
The first direct activator of BAX, a pro-apoptotic member the BCL-2 family, has been recently identified. Herein, structure-based lead optimization turned out into small series analogues, where 8 is most potent compound published so far. was used as pharmacological tool to ascertain, for time, anticancer potential BAX activators and obtained results would suggest that are future drugs rather than venoms.
We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as selective CXCR4 antagonist showing promising in vitro and vivo anticancer activity. However, further development this was hampered by its degradation biological fluids well low micromolar affinity for receptor. Herein, extensive chemical modifications led to new analogue (10) with enhanced potency, specificity, plasma stability. A combined approach Ala-amino acid scan, NMR, molecular modeling unraveled reasons...
Alzheimer's disease (AD) develops from a complex setting of genetic and biochemical alterations, including an increased level p53 in the brain. Here, robust specific activation by fibrillar non-β-amyloid component (NAC) AD was demonstrated human neuroblastoma SH-SY5Y cells. For first time, increase target gene transcription, cell cycle arrest, induction apoptosis elicited NAC were evidenced. These effects counterbalanced pifithrin-β, small molecule interfering with functions. Using structure...
In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through structure-activity relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO MDM2. As result, compound 9: (i) reactivated p53 functionality; (ii)...
The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number cancers. However, novel class small organic molecules, with BMS-202 (1) as lead, is emerging direct PD-L1 inhibitors. Herein, we report series 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized assayed for their binding NMR homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind protein challenged it co-culture...
Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells released soluble form by ADAM-17-mediated shedding. This process to EOC motility invasiveness, which reduced nonspecific inhibitors ADAM-17. For this reason, ADAM-17 may represent new useful target anticancer therapy. Herein, we report synthesis biological evaluation containing an...
Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means a kinetic mechanism in which two substrates Ado and ATP bind enzyme binary and/or ternary complex, with distinct protein conformations. Most described inhibitors have Ado-like structural motifs are nonselective, some them (e.g., tubercidine-like ligands) characterized toxic profile. We cloned expressed human AK (hAK) searched for novel non-substrate-like inhibitors. Our efforts widen diversity led...
Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed the insurgence of drug resistance mechanisms and presence subpopulation glioma stem cells (GSCs). GBM GSCs present, among others, an overexpression antiapoptotic proteins inhibition pro-apoptotic ones, which help escape apoptosis. Among inducers, Bcl-2 family protein Bax has recently emerged as promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106,...
Lipopolysaccharide (LPS) exposure to macrophages induces an inflammatory response, which is regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) RNA-binding protein that regulates cytokines chemokines transcripts containing AU/U-rich elements (AREs) mediates LPS-induced response. Here, we show small-molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages. TMs exist solution keto-enolic tautomerism, molecular dynamic...