Giulia Bononi

University of Pisa

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Carlotta Granchi

University of Pisa

Filippo Minutolo

University of Pisa

Tiziano Tuccinardi

University of Pisa

Giulio Poli

University of Pisa

Flavio Rizzolio

Ca' Foscari University of Venice

Marco Macchia

University of Pisa

Isabella Caligiuri

Centro di Riferimento Oncologico

Andrea Chicca

University of Bern

Jürg Gertsch

University of Bern

Valeria Di Bussolo

University of Pisa

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University of Pisa

Istituti di Ricovero e Cura a Carattere Scientifico

University of Siena

Centro di Riferimento Oncologico

University of Illinois Urbana-Champaign

Istituto di Farmacologia Traslazionale

Amsterdam UMC Location VUmc

Amsterdam University Medical Centers

University of Milan

University of Florence

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An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present)

Expert Opinion on Therapeutic Patents (2020)

Giulia Bononi Giulio Poli Flavio Rizzolio Tiziano Tuccinardi Marco Macchia

Introduction Monoacylglycerol lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradation of lipids in cancer cells enhances the availability of free fatty acids for new cellular membrane formation and pro-oncogenic lipid modulators. The multifaceted role of MAGL has greatly stimulated the search for MAGL inhibitors, which could be effective to treat diseases, such as inflammation, neurodegeneration and cancer.Areas covered This review covers patents published since 2018 up to now, concerning new MAGL inhibitors and their potential therapeutic applications.Expert opinion In the years 2018–2020, several well-known chemical scaffolds of MAGL inhibitors have been further optimized and developed and some new chemical classes have also been identified as MAGL inhibitors. Moreover, an increasing number of scientific publications covering MAGL inhibitors is focused on MAGL-specific positron emission tomography (PET) ligands. The numerous efforts of pharmaceutical companies and academic research groups finalized to find new potent MAGL inhibitors confirm that this research area is rapidly growing. Nevertheless, most of the patented compounds still belong to the large group of irreversible MAGL inhibitors, highlighting that the development of reversible MAGL inhibitors is still an unmet pharmaceutical need.

10.1080/13543776.2021.1841166

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Citations (30)

Monoacylglycerol lipase (MAGL) inhibitors based on a diphenylsulfide-benzoylpiperidine scaffold

European Journal of Medicinal Chemistry (2021)

Giulia Bononi Giacomo Tonarini Giulio Poli Ivana Barravecchia Isabella Caligiuri

Diacylglycerol lipase

10.1016/j.ejmech.2021.113679

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Citations (9)

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

Pharmaceuticals (2022)

Giulia Bononi Lorenzo Flori Valentina Citi Cecilia Acciai Viviana Nocilla

NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

Sirtuin 1

Moiety

SIRT2

10.3390/ph15030339

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Citations (3)

Enhanced activity of a pluronic F127 formulated Pin1 inhibitor for ovarian cancer therapy

Journal of Drug Delivery Science and Technology (2023)

Gloria Saorin Matteo Mauceri Enrico Cavarzerani Isabella Caligiuri Giulia Bononi

Cancer Therapy

10.1016/j.jddst.2023.104718

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Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

European Journal of Medicinal Chemistry (2020)

Carlotta Granchi Giulia Bononi Rebecca Ferrisi Eleonora Gori Giulia Mantini

10.1016/j.ejmech.2020.112857

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Citations (33)

New Phenylethanoid Glycosides from Cistanche phelypaea and Their Activity as Inhibitors of Monoacylglycerol Lipase (MAGL)

Planta Medica (2018)

Khadidja Aya Beladjila Djemaa Berrehal Nunziatina De Tommasi Carlotta Granchi Giulia Bononi

Four new phenylethanoid glycosides (1: -4: ), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (1: ), 1-β-p-hydroxyphenyl-ethyl-3,6-O-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (2: ), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (3: ), and 1-β-p-hydroxyphenyl-ethyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (4: ), together with three known compounds, were isolated from the n-butanol extract of Cistanche phelypaea aerial parts. The structural characterization of all compounds was performed by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments. The isolated compounds were assayed for their inhibitory activity on two enzymes involved in the peculiar glycolytic or lipidic metabolism of cancer cells, human lactate dehydrogenase (LDH), and monoacylglycerol lipase (MAGL), respectively. All the compounds showed negligible activity on LDH, whereas some of them displayed a certain inhibition activity on MAGL. In particular, compound 1: was the most active on MAGL, showing an IC50 value of 88.0 µM, and modeling studies rationalized the supposed binding mode of 1: in the MAGL active site.

IC50

Phenylethanoid

10.1055/s-0044-100187

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Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors

International Journal of Molecular Sciences (2022)

Miriana Di Stefano Salvatore Galati Gabriella Ortore Isabella Caligiuri Flavio Rizzolio

Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4, showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.

Identification

Cyclin-dependent kinase 5

10.3390/ijms231810653

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Citations (17)

Historical perspective of tumor glycolysis: A century with Otto Warburg

Seminars in Cancer Biology (2022)

Giulia Bononi Samuele Masoni Valeria Di Bussolo Tiziano Tuccinardi Carlotta Granchi

Warburg Effect

10.1016/j.semcancer.2022.07.003

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Citations (44)