{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:48:01Z","timestamp":1768567681413,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2\/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.<\/jats:p>","DOI":"10.3390\/ph13060113","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T04:09:03Z","timestamp":1591070943000},"page":"113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6221-6155","authenticated-orcid":false,"given":"Antonio","family":"Laghezza","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-5818","authenticated-orcid":false,"given":"Luca","family":"Piemontese","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-6639","authenticated-orcid":false,"given":"Leonardo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Caradonna","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5198-0051","authenticated-orcid":false,"given":"Mariangela","family":"Agamennone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, Via Dei Vestini, 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-5165","authenticated-orcid":false,"given":"Antonella","family":"Di Pizio","sequence":"additional","affiliation":[{"name":"Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3980-3180","authenticated-orcid":false,"given":"Giorgio","family":"Pochetti","sequence":"additional","affiliation":[{"name":"Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, Monterotondo Stazione, 00015 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Montanari","sequence":"additional","affiliation":[{"name":"Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, Monterotondo Stazione, 00015 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6716-3854","authenticated-orcid":false,"given":"Davide","family":"Capelli","sequence":"additional","affiliation":[{"name":"Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, Monterotondo Stazione, 00015 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2361-7364","authenticated-orcid":false,"given":"Marilena","family":"Tauro","sequence":"additional","affiliation":[{"name":"Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulvio","family":"Loiodice","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1358-7376","authenticated-orcid":false,"given":"Paolo","family":"Tortorella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, University of Bari \u201cA. Moro\u201d, via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bone.2010.06.007","article-title":"Matrix Metalloproteinases as Master Regulators of the Vicious Cycle of Bone Metastasis","volume":"48","author":"Lynch","year":"2011","journal-title":"Bone"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.semcancer.2017.11.008","article-title":"Matrix Metalloproteinases: A Challenging Paradigm of Cancer Management","volume":"56","author":"Alaseem","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2217\/17460816.3.3.253","article-title":"Is There a Final Common Pathway for Arthritis","volume":"3","author":"Malemud","year":"2008","journal-title":"Fut. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.2174\/1381612824666180604112925","article-title":"MMPs Are Involved in Osteoporosis and Are Correlated with Cardiovascular Diseases","volume":"24","author":"Azevedo","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G","article-title":"Skeletal Complications of Malignancy","volume":"80","author":"Coleman","year":"1997","journal-title":"Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"D\u2019Oronzo, S., Coleman, R., Brown, J., and Silvestris, F. (2019). Metastatic Bone Disease: Pathogenesis and Therapeutic Options: Up-Date on Bone Metastasis Management. J. Bone Oncol., 15.","DOI":"10.1016\/j.jbo.2018.10.004"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10585-019-09987-w","article-title":"Metastatic Dissemination Patterns of Different Primary Tumors to the Spine and Other Bones","volume":"36","author":"Onken","year":"2019","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrc867","article-title":"Metastasis to Bone: Causes, Consequences and Therapeutic Opportunities","volume":"2","author":"Mundy","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1056\/NEJMra030831","article-title":"Mechanisms of Bone Metastasis","volume":"350","author":"Roodman","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Guise, T.A., and Chirgwin, J.M. (2003). Transforming Growth Factor-Beta in Osteolytic Breast Cancer Bone Metastases. Clin. Orthop. Relat. Res., S32\u2013S38.","DOI":"10.1097\/01.blo.0000093055.96273.69"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1126\/science.1067100","article-title":"Matrix Metalloproteinase Inhibitors and Cancer: Trials and Tribulations","volume":"295","author":"Coussens","year":"2002","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1007\/s10555-014-9530-4","article-title":"New Approaches to Selectively Target Cancer-Associated Matrix Metalloproteinase Activity","volume":"33","author":"Tauro","year":"2014","journal-title":"Cancer Metastasis Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.tips.2013.02.004","article-title":"Missing the Target: Matrix Metalloproteinase Antitargets in Inflammation and Cancer","volume":"34","author":"Dufour","year":"2013","journal-title":"Trends Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fields, G.B. (2019). The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma. Cell, 8.","DOI":"10.3390\/cells8090984"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.2174\/0929867325666180326163523","article-title":"Mechanism and Inhibition of Matrix Metalloproteinases","volume":"26","author":"Cerofolini","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.2174\/1389450116666150113121733","article-title":"Phosphonate Emerging Zinc Binding Group in Matrix Metalloproteinase Inhibitors","volume":"16","author":"Campestre","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/ijc.20459","article-title":"Dosing and Scheduling Influence the Antitumor Efficacy of a Phosphinic Peptide Inhibitor of Matrix Metalloproteinases","volume":"113","author":"Dive","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1002\/cmdc.201000540","article-title":"Biphenyl Sulfonylamino Methyl Bisphosphonic Acids as Inhibitors of Matrix Metalloproteinases and Bone Resorption","volume":"6","author":"Rubino","year":"2011","journal-title":"ChemMedChem"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6456","DOI":"10.1016\/j.bmc.2013.08.054","article-title":"Arylamino Methylene Bisphosphonate Derivatives as Bone Seeking Matrix Metalloproteinase Inhibitors","volume":"21","author":"Tauro","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/j.bmcl.2014.03.001","article-title":"Arylamino Bisphosphonates: Potent and Selective Inhibitors of the Tumor-Associated Carbonic Anhydrase XII","volume":"24","author":"Tauro","year":"2014","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1016\/j.bmcl.2014.04.077","article-title":"Dual Carbonic Anhydrase\/Matrix Metalloproteinase Inhibitors Incorporating Bisphosphonic Acid Moieties Targeting Bone Tumors","volume":"24","author":"Tauro","year":"2014","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41827","DOI":"10.18632\/oncotarget.18103","article-title":"Selective Inhibition of Matrix Metalloproteinase-2 in the Multiple Myeloma-Bone Microenvironment","volume":"8","author":"Shay","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1158\/1535-7163.MCT-16-0315-T","article-title":"Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth","volume":"16","author":"Tauro","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tauro, M., and Lynch, C.C. (2018). Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis. Cancers (Basel), 10.","DOI":"10.3390\/cancers10060185"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"32628","DOI":"10.1074\/jbc.M806266200","article-title":"Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in Myeloma","volume":"283","author":"Purushothaman","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Owyong, M., Chou, J., van den Bijgaart, R.J., Kong, N., Efe, G., Maynard, C., Talmi-Frank, D., Solomonov, I., Koopman, C., and Hadler-Olsen, E. (2019). MMP9 Modulates the Metastatic Cascade and Immune Landscape for Breast Cancer Anti-Metastatic Therapy. Life Sci. Alliance, 2.","DOI":"10.26508\/lsa.201800226"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1242\/dmm.003160","article-title":"A Murine Model of Myeloma That Allows Genetic Manipulation of the Host Microenvironment","volume":"2","author":"Fowler","year":"2009","journal-title":"Dmm Dis. Model. Mech."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1021\/jm050787+","article-title":"Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates","volume":"49","author":"Pochetti","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bmcl.2005.09.057","article-title":"N-Hydroxyurea as Zinc Binding Group in Matrix Metalloproteinase Inhibition: Mode of Binding in a Complex with MMP-8","volume":"16","author":"Campestre","year":"2006","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1080\/14756366.2016.1217853","article-title":"Catechol-Based Matrix Metalloproteinase Inhibitors with Additional Antioxidative Activity","volume":"31","author":"Tauro","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_31","unstructured":"Schr\u00f6dinger LLC (2018). Schr\u00f6dinger Suite 2018-3: MacroModel, Glide, SiteMap, Maestro, Schr\u00f6dinger LLC."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ammazzalorso, A., De Filippis, B., Campestre, C., Laghezza, A., Marrone, A., Amoroso, R., Tortorella, P., and Agamennone, M. (2016). Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101768"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1007\/s00706-018-2237-4","article-title":"Mimic Catechins to Develop Selective MMP-2 Inhibitors","volume":"149","author":"Agamennone","year":"2018","journal-title":"Mon. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1021\/jm801166j","article-title":"Extra Binding Region Induced by Non-Zinc Chelating Inhibitors into the S 1 Subsite of Matrix Metalloproteinase 8 (MMP-8)","volume":"52","author":"Pochetti","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10205","DOI":"10.1021\/jm500505f","article-title":"Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1\u2019 Pocket in the Design of Selective, Small Molecule Inhibitors","volume":"57","author":"Fabre","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Southall, N.T., Dill, K.A., and Haymet, A.D.J. (2002). A View of the Hydrophobic Effect. J. Phys. Chem. B, 521\u2013533.","DOI":"10.1021\/jp015514e"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/6\/113\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:34:40Z","timestamp":1760175280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/6\/113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,1]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ph13060113"],"URL":"https:\/\/doi.org\/10.3390\/ph13060113","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,1]]}}}