{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:09:14Z","timestamp":1790629754146,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"FIRB, Bando Futuro in Ricerca 2010","doi-asserted-by":"publisher","award":["RBFR10ZJQT"],"award-info":[{"award-number":["RBFR10ZJQT"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"FIRB, Bando Futuro in Ricerca 2010","doi-asserted-by":"publisher","award":["PRA_2020_58"],"award-info":[{"award-number":["PRA_2020_58"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Pisa","award":["RBFR10ZJQT"],"award-info":[{"award-number":["RBFR10ZJQT"]}]},{"name":"University of Pisa","award":["PRA_2020_58"],"award-info":[{"award-number":["PRA_2020_58"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Intracellular pathogens, such as Chlamydia trachomatis, have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53\u2013MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2\u2013p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2\u2013p53 complex. Notably, RM37 reduced Chlamydia infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection.<\/jats:p>","DOI":"10.3390\/ph15111318","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T05:11:33Z","timestamp":1666761093000},"page":"1318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5376","authenticated-orcid":false,"given":"Elisa","family":"Nuti","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"La Pietra","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3087","authenticated-orcid":false,"given":"Simona","family":"Daniele","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-542X","authenticated-orcid":false,"given":"Doretta","family":"Cuffaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2762-1929","authenticated-orcid":false,"given":"Lidia","family":"Ciccone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-602X","authenticated-orcid":false,"given":"Chiara","family":"Giacomelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3456-4395","authenticated-orcid":false,"given":"Carolina","family":"Cason","sequence":"additional","affiliation":[{"name":"Unit of Advanced Microbiology Diagnosis and Translational Research, Institute for Maternal and Child Health-IRCCS \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7532-5449","authenticated-orcid":false,"given":"Alfonso","family":"Carotenuto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6460-3447","authenticated-orcid":false,"given":"Vincenzo Maria","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4762-8949","authenticated-orcid":false,"given":"Eleonora Da","family":"Pozzo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5051-1584","authenticated-orcid":false,"given":"Riccardo","family":"Di 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Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1038\/onc.2016.502","article-title":"Census and Evaluation of P53 Target Genes","volume":"36","author":"Fischer","year":"2017","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrc3711","article-title":"Unravelling Mechanisms of P53-Mediated Tumour Suppression","volume":"14","author":"Bieging","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","first-page":"603","article-title":"Tumour Incidence, Spectrum and Ploidy in Mice with a Large Deletion in the P53 Gene","volume":"9","author":"Purdie","year":"1994","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2014.01.021","article-title":"Mutant P53 in Cancer: New Functions and Therapeutic Opportunities","volume":"25","author":"Muller","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrc3430","article-title":"MDM2, MDMX and P53 in Oncogenesis and Cancer Therapy","volume":"13","author":"Wade","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Koo, N., Sharma, A.K., and Narayan, S. (2022). Therapeutics Targeting P53-MDM2 Interaction to Induce Cancer Cell Death. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095005"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1021\/jm501092z","article-title":"Small-Molecule Inhibitors of the MDM2\u2013P53 Protein\u2013Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment","volume":"58","author":"Zhao","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.1021\/acs.jmedchem.0c02188","article-title":"Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-P53 Protein\u2013Protein Interaction","volume":"64","author":"Chessari","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114334","DOI":"10.1016\/j.ejmech.2022.114334","article-title":"Small-Molecule MDM2 Inhibitors in Clinical Trials for Cancer Therapy","volume":"236","author":"Wang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1126\/science.1092472","article-title":"In Vivo Activation of the P53 Pathway by Small-Molecule Antagonists of MDM2","volume":"303","author":"Vassilev","year":"2004","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrmicro3537","article-title":"Modulation of P53 during Bacterial Infections","volume":"13","author":"Siegl","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.chom.2012.01.013","article-title":"Calpain Activation by the Shigella Flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium\u2019s Epithelial Niche","volume":"11","author":"Bergounioux","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.18632\/oncotarget.2828","article-title":"Helicobacter Pylori Bacteria Alter the P53 Stress Response via ERK-HDM2 Pathway","volume":"6","author":"Bhardwaj","year":"2015","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.celrep.2014.10.004","article-title":"Tumor Suppressor P53 Alters Host Cell Metabolism to Limit Chlamydia Trachomatis Infection","volume":"9","author":"Siegl","year":"2014","journal-title":"Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5201","DOI":"10.1038\/ncomms6201","article-title":"Chlamydia Infection Depends on a Functional MDM2-P53 Axis","volume":"5","author":"Rother","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.1021\/acs.jmedchem.5b01767","article-title":"Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2\/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas","volume":"59","author":"Daniele","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4749","DOI":"10.1038\/srep04749","article-title":"Apoptosis Therapy in Cancer: The First Single-Molecule Co-Activating P53 and the Translocator Protein in Glioblastoma","volume":"4","author":"Daniele","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1158\/1535-7163.MCT-08-0140","article-title":"Reactivation of P53 by a Specific MDM2 Antagonist (MI-43) Leads to P21-Mediated Cell Cycle Arrest and Selective Cell Death in Colon Cancer","volume":"7","author":"Shangary","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1021\/jm049137g","article-title":"Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate P53 in Cells","volume":"48","author":"Grasberger","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7044","DOI":"10.1021\/jm900681h","article-title":"Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2\u2013Tumor Protein 53 Protein\u2013Protein Interaction","volume":"52","author":"Allen","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.274.5289.948","article-title":"Structure of the MDM2 Oncoprotein Bound to the P53 Tumor Suppressor Transactivation Domain","volume":"274","author":"Kussie","year":"1996","journal-title":"Science"},{"key":"ref_24","unstructured":"Rossello, A., Nuti, E., Orlandini, E., Nencetti, S., Martini, C., Costa, B., Giacomelli, C., and Daniele, S. (2020). Compounds with a Benzo[a]Carbazole Structure and Use Thereof. (EP3,679,044A1), EU Patent."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/dta.1492","article-title":"An Antibody-Free Strategy for Screening Putative HDM2 Inhibitors Using Crude Bacterial Lysates Expressing GST-HDM2 Recombinant Protein","volume":"5","author":"Costa","year":"2013","journal-title":"Drug Test. Anal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4382","DOI":"10.1021\/jm070365v","article-title":"An NMR-Based Antagonist Induced Dissociation Assay for Targeting the Ligand\u2013Protein and Protein\u2013Protein Interactions in Competition Binding Experiments","volume":"50","author":"Krajewski","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13220","DOI":"10.1021\/ja052143x","article-title":"Monitoring the Effects of Antagonists on Protein\u2013Protein Interactions with NMR Spectroscopy","volume":"127","author":"Ozdowy","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6756","DOI":"10.1158\/0008-5472.CAN-06-0185","article-title":"HDJ-2 as a Target for Radiosensitization of Glioblastoma Multiforme Cells by the Farnesyltransferase Inhibitor R115777 and the Role of the P53\/P21 Pathway","volume":"66","author":"Wang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Villalonga-Planells, R., Coll-Mulet, L., Mart\u00ednez-Soler, F., Casta\u00f1o, E., Acebes, J.-J., Gim\u00e9nez-Bonaf\u00e9, P., Gil, J., and Tortosa, A. (2011). Activation of P53 by Nutlin-3a Induces Apoptosis and Cellular Senescence in Human Glioblastoma Multiforme. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018588"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Costa, B., Bendinelli, S., Gabelloni, P., Pozzo, E.D., Daniele, S., Scatena, F., Vanacore, R., Campiglia, P., Bertamino, A., and Gomez-Monterrey, I. (2013). Human Glioblastoma Multiforme: P53 Reactivation by a Novel MDM2 Inhibitor. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072281"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrm4007","article-title":"P53 in Survival, Death and Metabolic Health: A Lifeguard with a Licence to Kill","volume":"16","author":"Kruiswijk","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nrm3629","article-title":"Control of Cell Cycle Transcription during G1 and S Phases","volume":"14","author":"Bertoli","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1042\/BST20180444","article-title":"Glioblastoma Heterogeneity and the Tumour Microenvironment: Implications for Preclinical Research and Development of New Treatments","volume":"47","author":"Perrin","year":"2019","journal-title":"Biochem. Soc. Trans."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.farmac.2004.05.001","article-title":"Synthesis and Antimicrobial Activity of New 7\u03b2-(Benzo[a]Dihydrocarbazolyloxyacetyl)-Substituted Cephalosporins","volume":"59","author":"Rossello","year":"2004","journal-title":"Farmaco"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1111\/j.1462-5822.2006.00747.x","article-title":"Activation of the Host Cell Proinflammatory Interleukin-8 Response by Chlamydia Trachomatis","volume":"8","author":"Buchholz","year":"2006","journal-title":"Cell. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1034\/j.1600-0897.2003.01154.x","article-title":"Chemokine Bioactivity of RANTES Is Elevated in the Sera of Infertile Women with Past Chlamydia Trachomatis Infection","volume":"49","author":"Shibahara","year":"2003","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"450","DOI":"10.4049\/jimmunol.175.1.450","article-title":"Chlamydia Trachomatis Induces Expression of IFN-\u03b3-Inducible Protein 10 and IFN-\u03b2 Independent of TLR2 and TLR4, but Largely Dependent on MyD88","volume":"175","author":"Nagarajan","year":"2005","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.4161\/cc.9.6.10956","article-title":"Structures of Low Molecular Weight Inhibitors Bound to MDMX and MDM2 Reveal New Approaches for P53-MDMX\/MDM2 Antagonist Drug Discovery","volume":"9","author":"Popowicz","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D1045","DOI":"10.1093\/nar\/gkv1072","article-title":"BindingDB in 2015: A Public Database for Medicinal Chemistry, Computational Chemistry and Systems Pharmacology","volume":"44","author":"Gilson","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_40","unstructured":"Schr\u00f6dinger, L., and Warren, D. (2022, September 21). PyMOL 2020. Available online: https:\/\/pymol.org\/2\/#page-top."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/jmra.1995.1047","article-title":"Water Suppression That Works. Excitation Sculpting Using Arbitrary Wave-Forms and Pulsed-Field Gradients","volume":"112","author":"Hwang","year":"1995","journal-title":"J. Magn. Reson. Ser. A"},{"key":"ref_42","unstructured":"Rossello, A., Nuti, E., Orlandini, E., Nencetti, S., Martini, C., Costa, B., Giacomelli, C., and Daniele, S. (2019). Compounds with a Benzo[a]Carbazole Structure and Use Thereof. (WO2019049024A1)."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/11\/1318\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:02:58Z","timestamp":1760144578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/11\/1318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,26]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ph15111318"],"URL":"https:\/\/doi.org\/10.3390\/ph15111318","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,26]]}}}