Derivatives of D(-) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(-)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(-)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future.

Ligand-based design of anticancer MMP2 inhibitors: a review.

MMP2, a Zn2+-dependent metalloproteinase, is related to cancer and angiogenesis. Inhibition of this enzyme might result in a potential antimetastatic drug to leverage the anticancer drug armory. In silico or computer-aided ligand-based drug design is a method of rational drug design that takes multiple chemometrics (i.e., multi-quantitative structure-activity relationship methods) into account for virtually selecting or developing a series of probable selective MMP2 inhibitors. Though existing matrix metalloproteinase inhibitors have shown plausible pan-matrix metalloproteinase (MMP) activity, they have resulted in various adverse effects leading to their being rescinded in later phases of clinical trials. Therefore a review of the ligand-based designing methods of MMP2 inhibitors would result in an explicit route map toward successfully designing and synthesizing novel and selective MMP2 inhibitors.

Structure-Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors.

Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure-activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.

Engineered s-Triazine-Based Dendrimer-Honokiol Conjugates as Targeted MMP-2/9 Inhibitors for Halting Hepatocellular Carcinoma.

Despite the advances in developing MMP-2/9 inhibitors, off-target side effects and pharmacokinetics problems remain major challenges hindering their clinical success in cancer therapy. However, recent targeting strategies have clearly revitalized MMP research. Herein, we introduce new s-triazine-based dendrimers endowed with intrinsic MMP-2/9 inhibitory potential and tetherable to hepatocellular carcinoma-specific targeting ligands and anticancer agents via biodegradable linkages for targeted therapy. The designed dendrimeric platform was built with potential zinc-binding branching linkers (hydrazides) and termini (carboxylic acids and hydrazides) to confer potency against MMP-2/9. Preliminary cytotoxicity screening and MMP-2/9 inhibition assay of the free dendrimers revealed promising potency (MMP-9; IC50 =0.35-0.57 µM, MMP-2; IC50 =0.39-0.77 µM) within their safe doses (EC100 =94.15-42.75 µM). The hydrazide dendrimer was comparable to NNGH and superior to the carboxylic acid analogue. MTT assay showed that the free dendrimers were superior to the reference anticancer agent honokiol. Their anticancer potency was enhanced by HK conjugation, targeting ligands installation and PEGylation as exemplified by the hydrazide dendrimer conjugate (TPG3 -NH2 )-SuHK-FA-SuPEG (Huh-7; IC50 =5.54 µM, HepG-2; IC50 =10.07 µM) being 4 folds more active than HK, followed by the carboxylic acid conjugate (TPG3 -OH)-HK-LA-PEG (Huh-7; IC50 =14.97, HepG-2; IC50 =21.29 µM). This was consistent with apoptosis studies.

Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells.

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1' heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

Sodium hyaluronate-g-2-((N-(6-aminohexyl)-4-methoxyphenyl)sulfonamido)-N-hydroxyacetamide with enhanced affinity towards MMP12 catalytic domain to be used as visco-supplement with increased degradation resistance.

The present paper describes the functionalization of sodium hyaluronate (NaHA) with a small molecule (2-((N-(6-aminohexyl)-4-methoxyphenyl)sulfonamido)-N-hydroxyacetamide) (MMPI) having proven inhibitory activity against membrane metalloproteins involved in inflammatory processes (i.e. MMP12). The obtained derivative (HA-MMPI) demonstrated an increased resistance to the in-vitro degradation by hyaluronidase, viscoelastic properties close to those of healthy human synovial fluid, cytocompatibility towards human chondrocytes and nanomolar affinity towards MMP 12. Thus, HA-MMPI can be considered a good candidate as viscosupplement in the treatment of knee osteoarticular disease.

Halting colorectal cancer metastasis via novel dual nanomolar MMP-9/MAO-A quinoxaline-based inhibitors; design, synthesis, and evaluation.

Matrix metalloproteinase-9 (MMP-9) and monoamine oxidase-A (MAO-A) are central signaling nodes in CRC and promotors of distant metastasis associated with high mortality rates. Novel series of quinoxaline-based dual MMP-9/MAO-A inhibitors were synthesized to suppress CRC progression. The design rationale combines the thematic pharmacophoric features of MMP-9 and MAO-A inhibitors in hybrid scaffolds. All derivatives were initially screened via MTT assay for cytotoxic effects on normal colonocytes to assess their safety profiles, then evaluated for their anticancer potential on HCT116 cells overexpressing MMP-9 and MAO-A. The most promising derivatives 8, 16, 17, 19, and 28 exhibited single digit nanomolar IC50 against HCT116 cells within their safe doses (EC100) on normal colonocytes. They suppressed HCT116 cell migration by 73.32, 61.29, 21.27, 28.82, and 27.48%, respectively as detected by wound healing assay. Enzymatic assays revealed that the selected derivatives were superior to the reference MMP-9 and MAO-A inhibitors (quercetin and clorgyline, respectively). The nanomolar dual MMP-9/MAO-A inhibitor 19 was identified as the most potent and balanced dual inhibitor among the evaluated series with considerable selectivity against MAO-A over MAO-B. Besides, qRT-PCR analysis was conducted to explore the hit compounds' potential to downregulate hypoxia-inducing factor (HIF-1α) in HCT116 cells being correlated with MAO-A mediated CRC migration and invasion. The five above-mentioned compounds significantly downregulated HIF-1α by more than 5 folds. Docking simulations predicted their possible binding modes with MMP-9 and MAO-A and highlighted their essential structural features. Finally, they recorded drug-like in silico physicochemical parameters and ADMET profiles.

Inhibition of bacterial and human zinc-metalloproteases by bisphosphonate- and catechol-containing compounds.

Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and -14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S1'-subpocket, while these ringsystems entered the S2'- or S1 -subpockets or a region involving amino acids in the S1'- and S2'-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S1'-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2.

Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II.

A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.

Phosphonate as a Stable Zinc-Binding Group for "Pathoblocker" Inhibitors of Clostridial Collagenase H (ColH).

Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.

Targeted Delivery of a Matrix Metalloproteinases-2 Specific Inhibitor Using Multifunctional Nanogels to Attenuate Ischemic Skeletal Muscle Degeneration and Promote Revascularization.

Critical limb ischemia (CLI) is a severe form of peripheral artery disease (PAD). It is featured by degenerated skeletal muscle and poor vascularization. During the development of CLI, the upregulated matrix metalloproteinase-2 (MMP-2) degrades muscle extracellular matrix to initiate the degeneration. Meanwhile, MMP-2 is necessary for blood vessel formation. It is thus hypothesized that appropriate MMP-2 bioactivity in ischemic limbs will not only attenuate muscle degeneration but also promote blood vessel formation. Herein, we developed ischemia-targeting poly(N-isopropylacrylamide)-based nanogels to specifically deliver an MMP-2 inhibitor CTTHWGFTLC (CTT) into ischemic limbs to tailor MMP-2 bioactivity. Besides acting as an MMP-2 inhibitor, CTT promoted endothelial cell migration under conditions mimicking the ischemic limbs. The nanogels were sensitive to the pH of ischemic tissues, allowing them to largely aggregate in the injured area. To help reduce nanogel uptake by macrophages and increase circulation time, the nanogels were cloaked with a platelet membrane. An ischemia-targeting peptide CSTSMLKA (CST) was further conjugated on the platelet membrane for targeted delivery of nanogels into the ischemic area. CTT gradually released from the nanogels for 4 weeks. The nanogels mostly accumulated in the ischemic area for 28 days. The released CTT preserved collagen in the muscle and promoted its regeneration. In addition, CTT stimulated angiogenesis. Four weeks after CLI, the blood flow and vessel density of the ischemic limbs treated with the nanogels were remarkably higher than the control groups without CTT release. These results demonstrate that the developed nanogel-based CTT release system has the potential to stimulate ischemic limb regeneration.

Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.

Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.

Design of a dendrimer with a matrix metalloproteinase-responsive fluorescence probe and a tumor-homing peptide for metastatic tumor cell imaging in the lymph node.

Fluorescence imaging is a noninvasive technique for cancer diagnosis. Dendrimers are regularly branched macromolecules with highly controllable size and structure that are a potent multifunctional nanoparticle. Anionic-terminal polyamidoamine (PAMAM) dendrimers were previously found to be accumulated in the lymph node, which is one of the main routes of tumor metastasis. In this study, we designed and synthesized a dendrimeric imaging probe for lymph node-resident tumor cell imaging. A matrix metalloproteinase-2 (MMP-2)-responsive fluorescence peptide probe and a tumor-homing peptide were conjugated to the carboxy-terminal dendrimer. The dendrimeric imaging probe treatment showed fluorescence signals inside some tumor cells (e.g., human fibrosarcoma HT-1080 and breast cancer 4T1 cells), depending on the MMP activity, but not in macrophage-like RAW264 cells.

Discovery of 7-aminophenanthridin-6-one as a new scaffold for matrix metalloproteinase inhibitors with multitarget neuroprotective activity.

Matrix metalloproteinases (MMPs) are zinc-dependent hydrolytic enzymes of great biological relevance, and some of them are key to the neuroinflammatory events and the brain damage associated to stroke. Non-zinc binding ligands are an emerging trend in drug discovery programs in this area due to their lower tendency to show off-target effects. 7-Amino-phenanthridin-6-one is disclosed as a new framework able to inhibit matrix metalloproteinases by binding to the distal part of the enzyme S1' site, as shown by computational studies. A kinetic study revealed inhibition to be noncompetitive. Some of the compounds showed some degree of selectivity for the MMP-2 and MMP-9 enzymes, which are crucial for brain damage associated to ischemic stroke. Furthermore, some compounds also had a high neuroprotective activity against oxidative stress, which is also very relevant aspect of ischaemic stroke pathogenesis, both decreasing lipid peroxidation and protecting against the oxidative stress-induced reduction in cell viability. One of the compounds, bearing a 2-thienyl substituent at C-9 and a 4-methoxyphenylamino at C-7, had the best-balanced multitarget profile and was selected as a lead on which to base future structural manipulation.

Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.

Development of an antibacterial and anti-metalloproteinase dental adhesive for long-lasting resin composite restorations.

Despite all the advances in adhesive dentistry, dental bonds are still fragile due to degradation events that start during application of adhesive agents and the inherent hydrolysis of resin-dentin bonds. Here, we combined two outstanding processing methods (electrospinning and cryomilling) to obtain bioactive (antimicrobial and anti-metalloproteinase) fiber-based fillers containing a potent matrix metalloproteinase (MMP) inhibitor (doxycycline, DOX). Poly(ε)caprolactone solutions containing different DOX amounts (0, 5, 25, and 50 wt%) were processed via electrospinning, resulting in non-toxic submicron fibers with antimicrobial activity against Streptococcus mutans and Lactobacillus. The fibers were embedded in a resin blend, light-cured, and cryomilled for the preparation of fiber-containing fillers, which were investigated with antibacterial and in situ gelatin zymography analyzes. The fillers containing 0, 25, and 50 wt% DOX-releasing fibers were added to aliquots of a two-step, etch-and-rinse dental adhesive system. Mechanical strength, hardness, degree of conversion (DC), water sorption and solubility, bond strength to dentin, and nanoleakage analyses were performed to characterize the physico-mechanical, biological, and bonding properties of the modified adhesives. Statistical analyses (ANOVA; Kruskal-Wallis) were used when appropriate to analyze the data (α = 0.05). DOX-releasing fibers were successfully obtained, showing proper morphological architecture, cytocompatibility, drug release ability, slow degradation profile, and antibacterial activity. Reduced metalloproteinases (MMP-2 and MMP-9) activity was observed only for the DOX-containing fillers, which have also demonstrated antibacterial properties against tested bacteria. Adhesive resins modified with DOX-containing fillers demonstrated greater DC and similar mechanical properties as compared to the fiber-free adhesive (unfilled control). Concerning bonding performance to dentin, the experimental adhesives showed similar immediate bond strengths to the control. After 12 months of water storage, the fiber-modified adhesives (except the group consisting of 50 wt% DOX-loaded fillers) demonstrated stable bonds to dentin. Nanoleakage was similar among all groups investigated. DOX-releasing fibers showed promising application in developing novel dentin adhesives with potential therapeutic properties and MMP inhibition ability; antibacterial activity against relevant oral pathogens, without jeopardizing the physico-mechanical characteristics; and bonding performance of the adhesive.

Kaempferol tri- and tetrasaccharides from Camellia japonica seed cake and their inhibitory activities against matrix metalloproteinase-1 secretion using human dermal fibroblasts.

Eight kaempferol oligosaccharides were isolated and identified from Camellia japonica seed cake. The chemical structures of the isolates were determined by using chromatographic and spectroscopic techniques, such as high-performance liquid chromatography with a photodiode array detector (HPLC-PDA), one-dimensional (1H and 13C), and two-dimensional nuclear magnetic resonance (1H-1H COSY, HSQC and HMBC), ESI-Q-TOF-MS, and optical rotation. To evaluate the anti-aging efficacy of kaempferol oligosaccharides for cosmetic use, the MMP-1 inhibitory effects of the isolates were studied using human dermal fibroblasts which were cultured in HaCaT cell-conditioned media. The MMP-1 inhibitory assay results revealed that kaempferol-3-O-ß-d-xylopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 6)-O-ß-d-glucopyranosyl-(1 â†’ 2)-O-ß-d-glucopyranoside showed the most potent MMP-1 inhibitory activity. The basal level inhibition was 50 ppm, which indicated that C. japonica seed cake is a promising material for the development of anti-aging skin cosmetics.

Discovery of a d-pro-lys peptidomimetic inhibitor of MMP9: Addressing the gelatinase selectivity beyond S1' subsite.

Despite a high degree of structural similarity, it is known that MMP2 and MMP9 have distinct roles in the angiogenic switch and in cell migration, as they activate diverse signaling pathways. Indeed, inhibition of MMP2 and MMP9 can show beneficial or detrimental effects depending on the stage of tumor progression. Thus, the selective inhibition of gelatinases is of relevance for a successful drug lead, which has to be achieved despite the high structural similarity of the two gelatinases. Herein, the synthesis and evaluation of d-proline-derived hydroxamic acids containing amino appendages at C-4 as gelatinase inhibitors are reported. Inhibition assays enabled the identification of a > 200-fold selective MMP9 inhibitor when Lys was considered as a C-4 substituent, thus addressing gelatinase selectivity beyond the S1' subsite, which is a major driver for selectivity. Molecular docking studies revealed the basic moiety of Lys as detrimental for inhibition of MMP2 as compared to MMP9.

Carborane-Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron-Capture Therapy (BNCT).

Based on the previously reported potent and selective sulfone hydroxamate inhibitors SC-76276, SC-78080 (SD-2590), and SC-77964, potent MMP inhibitors have been designed and synthesized to append a boron-rich carborane cluster by employing click chemistry to target tumor cells that are known to upregulate gelatinases. Docking against MMP-2 suggests binding involving the hydroxamate zinc-binding group, key H-bonds by the sulfone moiety with the peptide backbone residues Leu82 and Leu83, and a hydrophobic interaction with the deep P1' pocket. The more potent of the two triazole regioisomers exhibits an IC50 of 3.7 nM versus MMP-2 and IC50 of 46 nM versus MMP-9.

Matrix Metalloproteinases (MMPs) in Targeted Drug Delivery: Synthesis of a Potent and Highly Selective Inhibitor against Matrix Metalloproteinase- 7.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed. AIMS: This study aims to comprehensively review the potentials and advances in applications of MMPs particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery. Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have shown significant targeting applicability at the genetic, protein, and activity levels in both physiological and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases at advanced cancer stages, which can be used for controlled release in cancers in advance stages. METHODS: Moreover, this study presents the synthesis and characteristics of a new and highly selective inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics and diagnostics modalities. RESULTS: Our findings showed that the structure of the inhibitor P3' side chains play the crucial role in developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities against ECM. CONCLUSION: Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following screening and optimization of the P3' side chains, with a Ki of 38.6 nM and an inhibitory selectivity of 575 of MMP-7 over MMP-1.