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.
Highlights
Matrix metalloproteinases (MMPs) are a family of 23 enzymes that control extracellular matrix (ECM) remodeling and act as key regulators of cancer-bone interactions in skeletal malignancy [1]
We have shown that the use of bisphosphonic-based bone-seeking MMP inhibitors (BMMPIs) makes the specific targeting of individual MMPs in the bone microenvironment a feasible strategy [18,19]
The most relevant difference between them resides in the number and type of residues of the omega-loop (13 for MMP-8 with respect to 11 of MMP-9) that determines differences in the bottom of the S1’ pocket
Summary
Matrix metalloproteinases (MMPs) are a family of 23 enzymes that control extracellular matrix (ECM) remodeling and act as key regulators of cancer-bone interactions in skeletal malignancy [1]. An imbalance of the MMP enzymatic activity/endogenous inhibitor ratio leads to irregular bone remodeling and tissue destruction These processes can occur under inflammatory conditions (periodontitis and rheumatoid arthritis) [3], in metabolic disorders (osteoporosis) [4], human genetic mutations, bone tumors, and bone metastases. Once tumors metastasize to bone, the disease becomes incurable, and patients may experience several skeletal-related complications, such as severe bone pain, hypercalcemia, nerve compression syndromes, and pathological fractures. This severely increases morbidity and diminishes the quality of life of the patients [7,8,9]
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