A5057560316- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Aldose Reductase and Taurine
- Cancer-related Molecular Pathways
- Cancer-related gene regulation
- Synthesis and Biological Evaluation
- Pharmacological Receptor Mechanisms and Effects
- Photosynthetic Processes and Mechanisms
- Prenatal Substance Exposure Effects
- Neuropeptides and Animal Physiology
- Estrogen and related hormone effects
- Polyamine Metabolism and Applications
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Genomics and Chromatin Dynamics
- Amino Acid Enzymes and Metabolism
- Synthesis and biological activity
- Click Chemistry and Applications
- DNA and Biological Computing
- Molecular Communication and Nanonetworks
- Bioactive Compounds and Antitumor Agents
- Synthesis of Tetrazole Derivatives
- Neuroblastoma Research and Treatments
- Heme Oxygenase-1 and Carbon Monoxide
Ospedale generale di zona San Camillo Treviso
2025
Ospedale per gli Infermi
2025
A. O. Ordine Mauriziano di Torino
2023
University of Turin
2023
Ospedale Policlinico San Martino
2023
University of Trieste
2023
European Institute of Oncology
1997-2020
Nerviano Medical Sciences
2004-2014
Pfizer (Italy)
2004
Istituto di Farmacologia Traslazionale
1997-2000
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities some receptor tyrosine relevant for cancer. inhibits all kinase family members shows dominant B inhibition-related cellular phenotype mechanism of action in cells vitro vivo. p53 status-dependent endoreduplication observed upon treatment PHA-739358, phosphorylation histone H3 Ser(10) inhibited. The compound has significant antitumor different xenografts spontaneous...
The optimization of a series 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition Aurora kinases led to identification compound 9d. This is potent inhibitor that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, efficacy in vivo tumor models, 9d was ultimately selected for further development.
Abstract Purpose: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile a novel, highly selective kinase inhibitor, PHA-680632, as candidate for anticancer therapy. Experimental Design: activity PHA-680632 assayed biochemical ATP competitive assay. A wide panel lines evaluated antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, Array Scan were used...
Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel versatile scaffold designed to target ATP pocket protein kinases. The most potent compound reported in this study had an IC(50) 0.027 microM enzymatic assay for Aur-A inhibition IC(50)s between 0.05 0.5 proliferation different tumor cell lines.
The discovery of a novel class inhibitors cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor CDKs but being poorly selective against panel serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity A2780 human ovarian carcinoma cells, optimization the physical properties pharmacokinetic profile led to identification highly potent orally available compounds. Compound 28...
We report the stereoselective synthesis and biological activity of a novel series tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors KDM1A. The new compounds strongly inhibit clonogenic potential acute leukemia cell lines. In particular three molecules (14d, 14e, 14g) showing selectivity versus MAO A remarkably inhibiting colony formation in THP-1 human cells, were assessed mouse for their preliminary pharmacokinetic. 14d 14e further tested vivo murine promyelocytic model,...
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). overexpressed in several tumor types, thus representing an emerging target for the development novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) identification thieno[3,2-b]pyrrole-5-carboxamides as reversible inhibitors KDM1A, whose preliminary exploration resulted compound 2 with biochemical IC50 = 160 nM. now report structure-guided optimization...
Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on high-throughput screening campaign performed KDM1A/CoREST, using time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The led 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, have prioritized the series of...
Three new series of tricyclic pyridazinones have been synthesized and tested in vitro order to assess (i) their ability inhibit aldose reductase enzyme (ALR2) (ii) specificity toward the target with respect other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, glutathione reductase. The inhibitory capability most effective compounds (IC50 values ranging from 6.44 12.6 microM) appears be associated a rather significant for ALR2. Molecular mechanics molecular...
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. inhibition through siRNA or prototype small molecules causes p53 independent apoptosis tumor cells while reversibly arresting cell cycle progression primary fibroblasts. This implies that could be considered potential target for anticancer therapy. We previously reported pyrrolopyridinones (e.g., 1) are potent and selective inhibitors kinase, with good cellular potency vitro ADME properties but...
Abstract Background Transthyretin cardiac amyloidosis (ATTR–CA) typically manifests with heart failure (HF). Discontinuing beta–blockers and avoiding angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) in patients ATTR–CA has been recommended. Methods We investigated the prescription of neurohormonal therapies their relationship all–cause mortality a multicenter cohort. Results: Patients (n=926) had median age 79 years (interquartile range 74–83), 90% were men,...
The results of recent clinical trials emphasise the importance an improved glycaemic control in diabetic patients order to prevent or at least delay long-term complications. difficulty obtaining normalisation blood glucose values has underlined search for new and effective aldose reductase inhibitors (ARIs) consequences elevated levels, therefore delaying onset retarding progression complications such as neuropathy, nephropathy, retinopathy cataract. Although physiological role (ALR2) not...
LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design effective covalent inhibitors, strategy to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series TCP analogs, carrying aroyl- arylacetylamino (1 a-h), Z-amino acylamino (2 a-o), or double-substituted benzamide (3 a-n) residues at the C4 C3 position phenyl ring. Further fragments obtained chemical manipulation...
A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or 8 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues potent natural analgesic epibatidine. When tested in hot plate assay, majority compounds showed significant effects, most interesting being 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At subcutaneous dose 1 mg/kg, 1a induced increase pain threshold, its action lasting for about 45 min. also...
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as transcription corepressor coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in past, main medicinal chemistry strategy toward inhibition was based on optimization ligands irreversibly bind FAD cofactor within catalytic site, we others have also identified reversible inhibitors. Herein reported...
The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to previously reported 5, 6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few lacking 5-acetyl group prepared. Several compounds derived from 2 displayed inhibitory properties comparable those Sorbinil. In this class...