Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Abstract

Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.

Uncovering chemical profiles, biological potentials, and protection effect against ECM destruction in H2O2‐treated HDF cells of the extracts of Stachys tundjeliensis

“…[ 79–81 ] MMP inhibitors, which were developed to prevent various diseases that may develop as a result of excessive expression of MMPs, have gained popularity in research. [ 82–84 ] Recent studies frequently mention plant‐derived natural MMP inhibitors and their promising results. [ 85–87 ] Due to the abundant antioxidants and phytochemicals within plants, the oxidative stress pathway implicated in MMP activation is effectively controlled, leading to a reduction in MMP levels to their basal state.…”

Extrapulmonary Comorbidities Associated with Chronic Obstructive Pulmonary Disease: A Review

“… 15 Although some MMP inhibitors were found to be safe in cancer trials, their success rate is relatively limited. 31 Therefore, large-scale prospective studies are still needed to further evaluate the safety and effectiveness of MMP inhibitors in COPD patients affected with CVD. It is noteworthy that numerous studies have demonstrated that both COPD and CVD share common mechanisms such as oxidative stress and systemic inflammation.…”

Potential of MMP-2 and MMP-9 Gelatinase Blockade as a Therapeutic Strategy in Fibrosarcoma Treatment: A Decadal Review

“…MMPs can be classified based on their substrate specificity, domain organization, and sequence homology into multiple major groups, including the following: collagenases (e.g., MMP-1, MMP-8, and MMP-13), which primarily degrade fibrillar collagens, which are critical components of the extracellular matrix; gelatinases (e.g., MMP-2 and MMP-9), which can degrade gelatin and denatured collagens, playing significant roles in cancer metastasis; stromelysins, which can degrade a variety of ECM proteins but have broad specificity (e.g., MMP-3 and MMP-10); and membrane-type MMPs (MT-MMPs), which are membrane-bound and participate in pericellular proteolysis, crucial for cell migration and other functions [21]. MMPs are typically secreted as inactive proenzymes and need to be activated extracellularly.…”

“…These newer inhibitors are designed to be more selective, aiming to reduce side effects and increase efficacy by specifically targeting MMP-2 and MMP-9. While the primary focus has been on the metastatic potential of cancers, MMP inhibitors also have the potential to improve outcomes by reducing angiogenesis and tumor growth [21]. In fibrosarcoma, where rapid and invasive growth is a major concern, inhibiting gelatinases can be particularly beneficial.…”