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用于治疗骨骼恶性肿瘤的趋骨性基质金属蛋白酶抑制剂

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

作者信息

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

机构信息

Department of Pharmacy and Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via Dei Vestini, 31, 66100 Chieti, Italy.

出版信息

Pharmaceuticals (Basel). 2020 Jun 1;13(6):113. doi: 10.3390/ph13060113.

DOI:10.3390/ph13060113
PMID:32492898
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7344628/
Abstract

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.

摘要

基质金属蛋白酶（MMPs）是一类参与癌症进展和转移不同阶段的酶。我们之前鉴定出了一类新型双膦酸抑制剂，它们对骨重塑至关重要的MMPs具有选择性，比如MMP-2。由于特定MMPs在肿瘤恶性发展的各个阶段的相关性日益增加，我们专注于提高对某些亚型的效力。在此，我们研究MMP-9，因为它在肿瘤侵袭、转移、血管生成和免疫反应中已被证实的作用，使其成为癌症治疗的理想靶点。通过计算分析，我们设计并表征了强效的MMP-2/MMP-9抑制剂。这是一种开发抑制剂并将其临床转化的有前景的方法，这些抑制剂可与标准护理疗法联合用于治疗骨骼恶性肿瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/9d1a4cf5c7cc/pharmaceuticals-13-00113-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/819c7c9a8868/pharmaceuticals-13-00113-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/a0ee507aa630/pharmaceuticals-13-00113-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/072473a2f3d1/pharmaceuticals-13-00113-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/14fe27de8deb/pharmaceuticals-13-00113-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/7eaa49d0f436/pharmaceuticals-13-00113-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/f5a1cd41d904/pharmaceuticals-13-00113-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/a650138385c4/pharmaceuticals-13-00113-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/9d1a4cf5c7cc/pharmaceuticals-13-00113-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/819c7c9a8868/pharmaceuticals-13-00113-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/a0ee507aa630/pharmaceuticals-13-00113-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/072473a2f3d1/pharmaceuticals-13-00113-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/14fe27de8deb/pharmaceuticals-13-00113-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/7eaa49d0f436/pharmaceuticals-13-00113-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/f5a1cd41d904/pharmaceuticals-13-00113-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/a650138385c4/pharmaceuticals-13-00113-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8de4/7344628/9d1a4cf5c7cc/pharmaceuticals-13-00113-g005.jpg

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Life Sci Alliance. 2019 Nov 14;2(6). doi: 10.26508/lsa.201800226. Print 2019 Dec.
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The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma.基质金属蛋白酶抑制剂的复兴：超越教条。
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Metastatic dissemination patterns of different primary tumors to the spine and other bones.不同原发肿瘤向脊柱和其他骨骼转移的扩散模式。
Clin Exp Metastasis. 2019 Dec;36(6):493-498. doi: 10.1007/s10585-019-09987-w. Epub 2019 Aug 16.
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Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management.转移性骨病：发病机制与治疗选择：骨转移管理的最新进展
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Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis.切入重点：基质金属蛋白酶-2活性如何控制乳腺癌向骨转移
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