A5080780327- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Protein Degradation and Inhibitors
- Chemical Reactions and Isotopes
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Chemistry and Chemical Engineering
- Ion Channels and Receptors
- Microbial Metabolic Engineering and Bioproduction
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Diet and metabolism studies
- Multiple Myeloma Research and Treatments
- Tryptophan and brain disorders
- Multicomponent Synthesis of Heterocycles
- Pharmacological Receptor Mechanisms and Effects
- Calcium signaling and nucleotide metabolism
- Amino Acid Enzymes and Metabolism
- Herbal Medicine Research Studies
- Bioactive Compounds and Antitumor Agents
- Enzyme Catalysis and Immobilization
- Metabolism and Genetic Disorders
- Dermatology and Skin Diseases
- Mass Spectrometry Techniques and Applications
- Histone Deacetylase Inhibitors Research
Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
2017-2024
University of Oxford
2021-2024
Science Oxford
2024
University of Turin
2024
Esteve Química (Spain)
2021-2022
Istituto di Farmacologia Traslazionale
2017
The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and degraders have progressed rapidly through pipelines. Despite advances made so far, their synthesis still represents a significant burden new approaches are highly demanded. Herein we report an unprecedented platform that leverages modular nature both multicomponent reactions enable preparation decorated PROTACs. As proof principle, our has been applied potential...
In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of novel class IDO1 inhibitors based on benzimidazole substructure. This family compounds is endowed with an extensive bonding network in protein active site, including interaction pocket C, region not commonly by previously reported inhibitors. The tight packing selected within enzyme contributes strong binding IDO1, inhibitory potency at low...
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and development of new capsaicinoids promising pharmacological approach management skin disorders related to inflammation pruritus. Here we report synthesis evaluation soft drugs that undergo deactivation by hydrolyzing activity esterases. The implanting ester group lipophilic moiety Passerini multicomponent reaction affords both agonists antagonists retain transient receptor potential vanilloid 1...
Abstract TRPV1, a member of the transient receptor potential (TRP) family, is nonselective calcium permeable ion channel gated by physical and chemical stimuli. In skin, TRPV1 plays an important role in neurogenic inflammation, pain pruritus associated to many dermatological diseases. Consequently, modulators could represent pharmacological tools respond patient needs that still unmet medical demand. Previously, we reported design capsaicinoid-based molecules undergo dermal deactivation...
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal and induce across plasma membrane) have been associated with number disorders, spanning from immune disorders acute pancreatitis suggested be druggable targets. present contribution, we exploited click chemistry approach synthesize class SOCE modulators where arylamide substructure characterizes most inhibitors so far described is...
IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared the last 10 years at vanguard of druggable targets cancer therapy due to its well-established role both immune escape and inflammatory neovascularization. Among pool IDO1 inhibitors that have entered clinical trials, none reached approval. The identification novel endowed with better profile, together further comprehension interactions residues active site, are still need. In this context, we synthesized class...
Abstract Activation of the phosphoinositide 3‐kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on‐target toxicity limits larger use. In particular, whereas tolerable acute treatment life‐threatening diseases, this less acceptable chronic conditions. past, strategy to overcome drawback was block selected isoforms mainly expressed leukocytes,...
Store-operated calcium entry (SOCE) is important in the maintenance of homeostasis and alterations this mechanism are responsible for several pathological conditions, including acute pancreatitis. Since discovery SOCE, many inhibitors have been identified extensively used as chemical probes to better elucidate role played by cellular mechanism. Nevertheless, only a few demonstrated drug-like properties so far. Here, we report class biphenyl triazoles among which stands out lead compound, 34,...
Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as myopathies. These lead to a wide spectrum defects, which usually include muscle weakness cramps. Negative modulators Ca2+-entry targeting wild-type have entered clinical trials different array...
Starting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points diversity, including sulfamide moiety 5-position. The synthetic procedure employs readily available starting materials proceeds smoothly under mild reaction conditions good tolerance for variety functional groups, coming to fill gap field compounds.
Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores Ca2+ upon depletion caused by opening Ca2+-channels. Gain-of-function mutations 2 key proteins store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated mouse model bearing p.I115F mutation recapitulates main features gain-of-function disorders: muscle weakness...
Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report doxophylline, a drug used in treatment asthma and COPD that undergoes extensive oxidative metabolism. Labeling main soft spots triggered an unexpected multidirectional that, while not improving pharmacokinetic parameters, changed scenario and, turn, pharmacodynamic features two murine models lung injury.
Abstract Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein interest that is fused short zinc finger (ZF) degron motif. These IMiDs, however, also endogenous neosubstrates, IKZF1 IKZF3. To improve selectivity, we took bump-and-hole approach design screen bumped IMiD analogs against 8380 ZF mutants. This yielded analog induces efficient mutant degron, while not affecting other cellular proteins, In...
A novel multicomponent reaction among arynes, tertiary α-monosubstituted α-isocyanoacetamides and water was discovered to access densely functionalized α-aroylamino amides. The stereoconservative course of the MCR investigated.