A5041001476- Chemokine receptors and signaling
- Histone Deacetylase Inhibitors Research
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Chemical Synthesis and Analysis
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Immunotherapy and Immune Responses
- Advanced biosensing and bioanalysis techniques
- DNA and Nucleic Acid Chemistry
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Receptor Mechanisms and Signaling
- Synthesis and biological activity
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- DNA Repair Mechanisms
- Lung Cancer Treatments and Mutations
- Genomics, phytochemicals, and oxidative stress
- HER2/EGFR in Cancer Research
- PARP inhibition in cancer therapy
University of Naples Federico II
2012-2025
Link Campus University
2024
University of Campania "Luigi Vanvitelli"
2016-2024
TU Dortmund University
2015-2017
Sapienza University of Rome
2011
Istituto Pasteur
2011
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed colocalize with the androgen receptor. We designed synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1–6 by coupling skeleton tranylcypromine 7, a known LSD1 inhibitor, 4-carboxy-4′-carbomethoxy-2,2′-bipyridine 8 5-carboxy-8-hydroxyquinoline 9, 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds able to simultaneously target both KDM...
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as dysregulation these elementary transducers extracellular signals, like epidermal growth factor receptor (EGFR), contributes to onset cancer, such non-small cell lung (NSCLC). Strong efforts were directed development irreversible inhibitors and led compound CO-1686, which takes advantage increased residence time at EGFR by alkylating Cys797 thereby preventing toxic effects. Here, we present a structure-based...
We investigated the ultrasonication-mediated effects on Fmoc-based solid-phase peptide synthesis (SPPS). Our study culminated with development of an ultrasound-assisted strategy (US-SPPS) that allowed for different biologically active peptides (up to 44-mer), a remarkable savings material and reaction time. Noteworthy, ultrasonic irradiation did not exacerbate main side reactions improved endowed "difficult sequences", placing US-SPPS among current high-efficient synthetic strategies.
Sirtuins are NAD+-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located mitochondria and a potential therapeutic target for cancer metabolic diseases, but no potent selective Sirt4 inhibitors have been reported. Here, we describe the identification of Sirt4-specific small-molecule inhibitors. Testing hits from target-based virtual screen revealed 12 active compounds. A focused based on two top compounds, followed by...
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process considered new approach for the treatment disease, in particular cancer neurological disorders. Therefore, novel small-molecule autophagy modulators are high demand. We describe discovery autophinib, potent inhibitor chemotype. Autophinib was identified by means phenotypic assay monitoring formation autophagy-induced puncta, indicating accumulation lipidated cytosolic protein LC3 on...
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks drastic change the treatment non-small cell lung (NSCLC). recurrent emergence resistance to these drugs requires development novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report optimization process for hit compound has emerged from phenotypic screen resulting indazole-based compounds. These inhibitors are...
Epigenetics is nowadays a well-accepted area of research. In the last years, tremendous progress was made regarding molecules targeting EZH2, directly or indirectly. Recently tazemetostat hit market after FDA-approval for treatment lymphoma. However, impairment EZH2 activity by orthosteric intervention has proven to be effective only in limited subset cancers. Considering multiproteic nature PRC2 complex and marked dependence functions on other core subunits such as EED, recent new approach...
Identification of integrins as cancer targets has stimulated the development specific inhibitory ligands. However, following cilengitide′s unexpected clinical failure by promoting angiogenesis at low concentrations, pure ligand antagonism was soon scrutinized. We evaluated αvβ3, αvβ6, or α5β1 ligands for concentration-dependent functional switches in respective integrin subtype-overexpressing cells. Cilengitide (L2) L1 provoked minor transient changes (p)-FAK and (p)-p44/42(erk-1/2)...
KAT8 is a lysine acetyltransferase primarily catalyzing the acetylation of Lys16 histone H4 (H4K16). dysregulation linked to development and metastatization many cancer types, including non-small cell lung (NSCLC) acute myeloid leukemia (AML). Few inhibitors have been reported so far, none which displaying selective activity. Based on KAT3B/KDAC inhibitor C646, we developed series N-phenyl-5-pyrazolone derivatives identified compounds 19 34 as low-micromolar over panel KATs KDACs. Western...
Monoamine oxidases (MAOs) are involved in various psychiatric and neurodegenerative disorders; hence, MAO inhibitors useful agents the therapy of Parkinson's disease, Alzheimer's dementia, depression syndrome. Herein we report a novel series 3-(1H-pyrrol-3-yl)-2-oxazolidinones 3-7 as reversible, highly potent selective anti-MAO-A agents. In particular, 4b, 5b, 4c showed K(i-MAO-A) 0.6, 0.8, 1 nM, respectively, being 200000-fold for MAO-A with respect to MAO-B.
Abstract The RGD‐recognizing αvβ6 integrin has only recently emerged as a major target for cancer diagnosis and therapy. Thus, the development of selective, low‐molecular‐weight ligands this receptor is still in great demand. Here, metadynamics‐driven design strategy allowed us to successfully convert helical nonapeptide into cyclic pentapeptide ( 6 ) showing remarkable potency specificity. NMR docking studies elucidated reasons high affinity selectivity compound, setting ground rational new...
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...
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Abstract Despite progress in the prevention and diagnosis of cancer, current technologies for tumor detection present several limitations including invasiveness, toxicity, inaccuracy, lengthy testing duration high cost. Therefore, innovative diagnostic techniques that integrate knowledge from biology, oncology, medicinal analytical chemistry are now quickly emerging attempt to address these issues. Following this approach, here we developed a paper-based electrochemical device detecting...
Abstract Chemical manipulations performed on 2‐methyl‐3‐carbethoxyquinoline ( 1 ), a histone acetyltransferase inhibitor previously identified by our research group and active at the sub‐millimolar/millimolar level, led to compounds bearing higher alkyl groups C2‐quinoline or additional side chains C6‐quinoline positions. Such displayed least threefold improved inhibitory potency toward p300 protein lysine activity; some of them decreased H3 H4 acetylation levels in U937 cells induced high...
In our ongoing pursuit of CXCR4 antagonists as potential anticancer agents, we recently developed a potent, selective, and plasma stable peptide, Ac-Arg-Ala-[d-Cys-Arg-Phe-Phe-Cys]-COOH (3). Nevertheless, this compound was still not potent enough (IC50 ≈ 53 nM) to enter preclinical studies. Thus, lead-optimization campaign here undertaken further improve the binding affinity 3 while preserving its selectivity proteolytic stability. Specifically, extensive structure-activity relationships...
Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation a peptidic ligand within membrane receptor such as GPCR is great impact for rational drug design more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study interaction peptide heptamers, derived from C-X-C Motif Chemokine 12 (CXCL12), Receptor Type 4 (CXCR4) on...
Herein, we developed an innovative and easily accessible solid-phase synthetic protocol for Peptide Nucleic Acid (PNA) oligomers by systematically investigating the ultrasonication effects in all steps of PNA synthesis (US-PNAS). When compared with standard protocols, application so-obtained US-PNAS approach succeeded improving crude product purities isolated yields different PNA, including small or medium-sized (5-mer 9-mer), complex purine-rich sequences (like a 5-mer Guanine homoligomer...
Nucleopeptides are promising nucleic acid mimetics in which the peptide backbone bears nucleobases. They can recognize DNA and RNA targets modulating their biological functions. To date, lack of an effective strategy for synthesis nucleopeptides prevents evaluation biomedical applications. Herein, we describe unprecedented approach that enables cationic both homo heterosequence wholly on solid support with high yield purity. Spectroscopic studies indicate advantageous properties terms...
In the fight against Glioblastoma Multiforme, recent literature data have highlighted that integrin α5β1 and p53 are part of convergent pathways in control glioma apoptosis. This observation prompted us to seek a molecule able simultaneously modulate both target families. Analyzing results previous virtual screening murine double minute 2 protein (MDM2), we envisaged Arg-Gly-Asp (RGD)-mimetic molecules could be inhibitors MDM2/4. Herein, present discovery compound 7, which inhibits MDM2/4...
Abstract Herein we report novel pyrrole‐ and benzene‐based hydroxamates ( 8 , 10 ) 2′‐aminoanilides 9 11 bearing the tert ‐butylcarbamate group at CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds b c selectively inhibited HDAC6 nanomolar level, whereas other effected an increase in acetyl‐α‐tubulin levels human acute myeloid leukemia U937 cells. In same cell line, compounds elicited 18.4 21.4 % apoptosis, respectively (SAHA: 16.9 %), pyrrole anilide displayed highest...
The recently reported CXCR4 antagonist 3 (Ac-Arg-Ala-[DCys-Arg-2Nal-His-Pen]-CO2H) was investigated as a molecular scaffold for CXCR4-targeted positron emission tomography (PET) tracer. Toward this end, functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononanetriacetic (NOTA). On the basis of convincing affinity data, both tracers, [68Ga]NOTA analogue ([68Ga]-5) [68Ga]DOTA ([68Ga]-4), were evaluated PET imaging in "in vivo" models...