Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

Laghezza, Antonio; Piemontese, Luca; Brunetti, Leonardo; Caradonna, Alessia; Agamennone, Mariangela; Pizio, Antonella Di; Pochetti, G.; Montanari, R.; Capelli, Davide; Tauro, Marilena; Loiodice, Fulvio; Tortorella, Paolo

doi:10.3390/ph13060113

Cited by 2 publications

(3 citation statements)

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“…For this reason, moreover, the binding mode obtained for these ligands in all MMPs is not well conserved; one phosphonic group coordinates the zinc ion following the crystallographic tetrahedral geometry, while the other can line up to the binding mode observed in the X-ray complex [ 18 ] for some ligands. At the same time, for other ligands, the second phosphonic group reaches Leu164 and Ala165 NHs, providing key H-bonds and allowing the aromatic group to reach deeper in the S1′ site, as observed for arylamino-derivatives that possess the same structural frame [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

“…Lead compound ML115 showed high potency and was also endowed with antiosteoclastic activity, which could reduce skeletal disease burden in patients with conditions involving abnormal bone resorption [ 8 , 17 ]. Further developments along this line of research showed that modifications on the arylbisphosphonic scaffold could afford compounds which selectively inhibit MMP-2 [ 8 , 15 , 17 ] and MMP-9 [ 18 ], and that also exhibit significant potential for bone malignancy therapy, being superior at promoting cancer apoptosis than standard-of-care bisphosphonates, such as zoledronic acid [ 8 , 17 ]. Moreover, these bisphosphonic MMPIs (BMMPIs) showed no particular side effects in vivo at therapeutic dosages [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

et al. 2021

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Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

et al. 2021

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“…Laghezza and his colleagues have designed a bisphosphonic acid inhibitor, ML 115. [ 16 ] This substance is based on sulfonamide, which is treated with diethyl phosphite to obtain a series of aromatic bisphosphonic acid derivatives. These bisphosphonic acid derivatives target tumor cells by interacting with the side chains of MMPs at specific sites due to the different bonding mechanisms of the two phosphine groups.…”

Section: Materials and Methods: Nanomaterials Applied To Tme Response...mentioning

confidence: 99%

Tumor Therapy Strategies Based on Microenvironment‐Specific Responsive Nanomaterials

Zhang

Ding

Sun

et al. 2023

Adv Healthcare Materials

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The tumor microenvironment (TME) is a complex and variable region characterized by hypoxia, low pH, high redox status, overexpression of enzymes, and high‐adenosine triphosphate concentrations. In recent years, with the continuous in‐depth study of nanomaterials, more and more TME‐specific response nanomaterials are used for tumor treatment. However, the complexity of the TME causes different types of responses with various strategies and mechanisms of action. Aiming to systematically demonstrate the recent advances in research on TME‐responsive nanomaterials, this work summarizes the characteristics of TME and outlines the strategies of different TME responses. Representative reaction types are illustrated and their merits and demerits are analyzed. Finally, forward‐looking views on TME‐response strategies for nanomaterials are presented. It is envisaged that such emerging strategies for the treatment of cancer are expected to exhibit dramatic trans‐clinical capabilities, demonstrating the extensive potential for the diagnosis and therapy of cancer.

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Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

Cited by 2 publications

References 35 publications

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

Tumor Therapy Strategies Based on Microenvironment‐Specific Responsive Nanomaterials

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