المؤلفون: Creighton, Samantha D. (ORCID 0000-0002-3463-2394), Jardine, Kristen H., Desimone, Alexa, Zmetana, Megan, Castellano, Sabrina, Milite, Ciro, Sbardella, Gianluca (ORCID 0000-0003-0748-1145), Winters, Boyer D.

المصدر: Learning & Memory. Mar 2022 29(3):71-76.

تمت مراجعته من قبل الزملاء: Y

Page Count: 6

الواصفات: Alzheimers Disease, Animals, Research, Spatial Ability, Memory, Age Differences, Intervention, Biochemistry

مستخلص: Histone acetylation, catalyzed by e, has emerged as a promising therapeutic strategy in Alzheimer's disease (AD). By longitudinally characterizing spatial memory at 3, 6, and 9 mo of age, we show that acute activation and inhibition of the histone acetyltransferase PCAF remediated memory impairments in 3xTG-AD mice in an age-related bidirectional manner. At 3 and 6 mo of age, PCAF activation ameliorated memory deficits. At 9 mo of age, PCAF activation had no effect on spatial memory, whereas PCAF inhibition improved memory deficits in females. This work reveals a complex potential therapeutic role for PCAF in AD, initially benefitting memory but becoming detrimental as the disease progresses.

Abstractor: As Provided

المؤلفون: Auberson, Yves, P, Arimondo, Paola, B, Duca, Maria, Essig, Sebastian, Grether, Uwe, Rufer, Arne, Sbardella, Gianluca, Schopfer, Ulrich, Torrens, Antoni, van der Stelt, Mario, Vauzeilles, Boris, Vázquez, Olalla, Zhang, Andrew

المساهمون: Novartis Institutes for BioMedical Research (NIBR), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA), Bayer AG Wuppertal, Germany, F. Hoffmann-La Roche Basel, Università degli Studi di Salerno = University of Salerno (UNISA), ABAC Therapeutics Barcelona, Universiteit Leiden = Leiden University, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie - CNRS Chimie (INC-CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Philipps Universität Marburg = Philipps University of Marburg, AstraZeneca US Waltham, USA, AstraZeneca Cambridge, UK

المصدر: ISSN: 1439-4227.

مصطلحات موضوعية: [CHIM.THER]Chemical Sciences/Medicinal Chemistry

الوصف: International audience ; Ground‐breaking research in disease biology and continuous efforts in method development have uncovered a range of potential new drug targets. Increasingly, the drug discovery process is informed by technologies involving chemical probes as tools. Applications for chemical probes comprise target identification and assessment, as well as the qualification of small molecules as chemical starting points and drug candidates. Progress in probe chemistry has opened the way to novel assay formats and pharmaceutical compound classes. The European Federation of Medicinal Chemistry and Chemical Biology (EFMC) has launched the Chemical Biology Initiative to advance science in the field of medicinal chemistry and chemical biology, while representing all members of this extended scientific community. This review provides an overview of the many important developments in the field of chemical biology that have happened at the lively interface of academic and industrial research.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36704975; hal-04278306; https://hal.science/hal-04278306Test; https://hal.science/hal-04278306/documentTest; https://hal.science/hal-04278306/file/EFMC%20trends%20in%20MCCB.pdfTest; PUBMED: 36704975

الإتاحة: https://doi.org/10.1002/cbic.202200690Test
https://hal.science/hal-04278306Test
https://hal.science/hal-04278306/documentTest
https://hal.science/hal-04278306/file/EFMC%20trends%20in%20MCCB.pdfTest

المؤلفون: Fiorentino, Francesco, Sementilli, Sara, Menna, Martina, Turrisi, Federica, Tomassi, Stefano, Pellegrini, Francesca Romana, Iuzzolino, Angela, D’Acunzo, Francesca, Feoli, Alessandra, Wapenaar, Hannah, Taraglio, Sophie, Fraschetti, Caterina, Del Bufalo, Donatella, Sbardella, Gianluca, Dekker, Frank J., Paiardini, Alessandro, Trisciuoglio, Daniela, Mai, Antonello, Rotili, Dante

المصدر: Fiorentino , F , Sementilli , S , Menna , M , Turrisi , F , Tomassi , S , Pellegrini , F R , Iuzzolino , A , D’Acunzo , F , Feoli , A , Wapenaar , H , Taraglio , S , Fraschetti , C , Del Bufalo , D , Sbardella , G , Dekker , F J , Paiardini , A , Trisciuoglio , D , Mai , A & Rotili , D 2023 , ' First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8 ' , Journal of Medicinal Chemistry , vol. 66 , ....

الوصف: KAT8 is a lysine acetyltransferase primarily catalyzing the acetylation of Lys16 of histone H4 (H4K16). KAT8 dysregulation is linked to the development and metastatization of many cancer types, including non-small cell lung cancer (NSCLC) and acute myeloid leukemia (AML). Few KAT8 inhibitors have been reported so far, none of which displaying selective activity. Based on the KAT3B/KDAC inhibitor C646, we developed a series of N-phenyl-5-pyrazolone derivatives and identified compounds 19 and 34 as low-micromolar KAT8 inhibitors selective over a panel of KATs and KDACs. Western blot, immunofluorescence, and CETSA experiments demonstrated that both inhibitors selectively target KAT8 in cells. Moreover, 19 and 34 exhibited mid-micromolar antiproliferative activity in different cancer cell lines, including NSCLC and AML, without impacting the viability of nontransformed cells. Overall, these compounds are valuable tools for elucidating KAT8 biology, and their simple structures make them promising candidates for future optimization studies.

وصف الملف: application/pdf

العلاقة: https://research.rug.nl/en/publications/7ca47a3f-7ab9-4c7b-a739-7961d690ede8Test

الإتاحة: https://doi.org/10.1021/acs.jmedchem.2c01937Test
https://hdl.handle.net/11370/7ca47a3f-7ab9-4c7b-a739-7961d690ede8Test
https://research.rug.nl/en/publications/7ca47a3f-7ab9-4c7b-a739-7961d690ede8Test
https://pure.rug.nl/ws/files/688529096/acs.jmedchem.2c01937.pdfTest
http://www.scopus.com/inward/record.url?scp=85159627845&partnerID=8YFLogxKTest

المؤلفون: Cipriano, Alessandra, Viviano, Monica, Feoli, Alessandra, Milite, Ciro, Sarno, Giuliana, Castellano, Sabrina, Sbardella, Gianluca

المساهمون: Ministero dell'Universit? e della Ricerca

المصدر: Journal of Medicinal Chemistry ; volume 66, issue 17, page 11632-11655 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.3c00770Test

المؤلفون: Feoli, Alessandra, Iannelli, Giulia, Cipriano, Alessandra, Milite, Ciro, Shen, Lei, Wang, Zhihao, Hadjikyriacou, Andrea, Lowe, Troy L., Safaeipour, Cyrus, Viviano, Monica, Sarno, Giuliana, Morretta, Elva, Monti, Maria Chiara, Yang, Yanzhong, Clarke, Steven G., Cosconati, Sandro, Castellano, Sabrina, Sbardella, Gianluca

المساهمون: Division of Molecular and Cellular Biosciences, Ministero dell’Istruzione, dell’Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Università degli Studi di Salerno, National Institute of General Medical Sciences, Regione Campania

المصدر: Journal of Medicinal Chemistry ; volume 66, issue 19, page 13665-13683 ; ISSN 0022-2623 1520-4804

مصطلحات موضوعية: Drug Discovery, Molecular Medicine

الإتاحة: https://doi.org/10.1021/acs.jmedchem.3c01030Test

المؤلفون: Viviano, Monica, Cipriano, Alessandra, Fabbrizi, Emanuele, Feoli, Alessandra, Castellano, Sabrina, Sbardella, Gianluca, Mai, Antonello, Milite, Ciro, Rotili, Dante

المساهمون: Viviano, Monica, Cipriano, Alessandra, Fabbrizi, Emanuele, Feoli, Alessandra, Castellano, Sabrina, Sbardella, Gianluca, Mai, Antonello, Milite, Ciro, Rotili, Dante

مصطلحات موضوعية: BD1, BET, Epigenetic, bromodomain, cancer, selective inhibition, small molecule modulators

الوصف: Introduction: Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity. Mounting evidence suggests that BD1 is primarily involved in cancer and that its selective inhibition can phenocopy the anticancer effects of pan-BETi with increased tolerability. Therefore, the development of BD1 selective inhibitors is highly pursed in both academia and industry. Areas covered: This review aims at giving an overview of the patent literature of BD1-selective BETi between 2014 and 2023. WIPO, USPTO, EPO, and SciFinder® databases were used for the search of patents. Expert opinion: The development of BD1-selective BETi, despite challenging, is highly desirable as it could have a great impact on the development of new safer anticancer therapeutics. Several strategies could be applied to discover potent and selective compounds with limited side effects.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38465537; firstpage:1; lastpage:17; numberofpages:17; journal:EXPERT OPINION ON THERAPEUTIC PATENTS; https://hdl.handle.net/11386/4859652Test

الإتاحة: https://doi.org/10.1080/13543776.2024.2327300Test
https://hdl.handle.net/11386/4859652Test

المؤلفون: Feoli, Alessandra, Sarno, Giuliana, Castellano, Sabrina, Sbardella, Gianluca

المساهمون: Feoli, Alessandra, Sarno, Giuliana, Castellano, Sabrina, Sbardella, Gianluca

مصطلحات موضوعية: DMSO, DMSO effect, biophysical characterization, epigenetic, ligand affinity

الوصف: Being the standard solvent for preparing stock solutions of compounds for drug discovery, DMSO is always present in assay buffers in concentrations ranging from 0.1% to 5% (v/v). Even at the lowest concentrations, DMSO-containing solutions can have significant effects on individual proteins and possible pitfalls cannot be eliminated. Herein, we used two protein systems, the lysine methyltransferases G9a/KMT1C and SETD8/KMT5A, to study the effects of DMSO on protein stability and on the binding of the corresponding inhibitors, using different biophysical methods such as nano Differential Scanning Fluorimetry (nanoDSF), Differential Scanning Fluorimetry (DSF), microscale thermophoresis (MST), and surface plasmon resonance (SPR), all widely used in drug discovery screening campaigns. We demonstrated that the effects of DMSO are protein- and technique-dependent and cannot be predicted or extrapolated on the basis of previous studies using different proteins and/or different assays. Moreover, we showed that the application of orthogonal biophysical methods can lead to different binding affinity data, thus confirming the importance of using at least two different orthogonal assays in screening campaigns. This variability should be taken into account in the selection and characterization of hit compounds, in order to avoid data misinterpretation.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38205880; info:eu-repo/semantics/altIdentifier/wos/WOS:001148333600001; volume:25; firstpage:e202300809; lastpage:e202300809; numberofpages:11; journal:CHEMBIOCHEM; https://hdl.handle.net/11386/4853735Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85183041993

الإتاحة: https://doi.org/10.1002/cbic.202300809Test
https://hdl.handle.net/11386/4853735Test

المؤلفون: Milite, Ciro, Sarno, Giuliana, Pacilio, Ida, Cianciulli, Agostino, Viviano, Monica, Iannelli, Giulia, Gazzillo, Erica, Feoli, Alessandra, Cipriano, Alessandra, Giovanna Chini, Maria, Castellano, Sabrina, Bifulco, Giuseppe, Sbardella, Gianluca

المصدر: ChemMedChem ; ISSN:1860-7187

مصطلحات موضوعية: Arginine mimics, Bioisosterism, PRMT4 inhibitors, Prodrugs, pyrrole

الوصف: Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate-competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)-Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on-target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine-amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo.

العلاقة: https://doi.org/10.1002/cmdc.202400139Test; https://pubmed.ncbi.nlm.nih.gov/38752332Test

الإتاحة: https://doi.org/10.1002/cmdc.202400139Test
https://pubmed.ncbi.nlm.nih.gov/38752332Test

المؤلفون: Cipriano, Alessandra, Milite, Ciro, Feoli, Alessandra, Viviano, Monica, Pepe, Giacomo, Campiglia, Pietro, Sarno, Giuliana, Picaud, Sarah, Imaide, Satomi, Makukhin, Nikolai, Filippakopoulos, Panagis, Ciulli, Alessio, Castellano, Sabrina, Sbardella, Gianluca

المصدر: Cipriano , A , Milite , C , Feoli , A , Viviano , M , Pepe , G , Campiglia , P , Sarno , G , Picaud , S , Imaide , S , Makukhin , N , Filippakopoulos , P , Ciulli , A , Castellano , S & Sbardella , G 2022 , ' Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain ' , ChemMedChem , vol. 17 , no. 20 , e202200343 . https://doi.org/10.1002/cmdc.202200343Test

مصطلحات موضوعية: Benzimidazole-6-sulfonamide, Bromodomain, Bioisosteres, Selectivity, Structure-activity relationships

الوصف: The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N -terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

وصف الملف: application/pdf

العلاقة: https://discovery.dundee.ac.uk/en/publications/9262919b-076d-4f3a-b6e8-482a936747cdTest

الإتاحة: https://doi.org/10.1002/cmdc.202200343Test
https://discovery.dundee.ac.uk/en/publications/9262919b-076d-4f3a-b6e8-482a936747cdTest
https://discovery.dundee.ac.uk/ws/files/86582869/ChemMedChem_2022_Cipriano_Discovery_of_Benzo_d_imidazole_6_sulfonamides_as_Bromodomain_and_Extra_Terminal_Domain_BET.pdfTest
http://www.scopus.com/inward/record.url?scp=85138079605&partnerID=8YFLogxKTest

المؤلفون: Iannelli, Giulia, Milite, Ciro, Marechal, Nils, Cura, Vincent, Bonnefond, Luc, Troffer-Charlier, Nathalie, Feoli, Alessandra, Rescigno, Donatella, Wang, Yalong, Cipriano, Alessandra, Viviano, Monica, Bedford, Mark, Cavarelli, Jean, Castellano, Sabrina, Sbardella, Gianluca

المساهمون: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

المصدر: ISSN: 0022-2623.

مصطلحات موضوعية: [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology

الوصف: Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.

العلاقة: hal-04116086; https://hal.science/hal-04116086Test; https://hal.science/hal-04116086/documentTest; https://hal.science/hal-04116086/file/islandora_163785.pdfTest

الإتاحة: https://doi.org/10.1021/acs.jmedchem.2c00252Test
https://hal.science/hal-04116086Test
https://hal.science/hal-04116086/documentTest
https://hal.science/hal-04116086/file/islandora_163785.pdfTest