Outline of gelatinase inhibitors as anti-cancer agents: A patent mini-review for 2010-present

Baidya, Sandip Kumar; Amin, Sk. Abdul; Jha, Tarun

doi:10.1016/j.ejmech.2020.113044

Cited by 19 publications

(16 citation statements)

References 85 publications

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“…These inhibitors include the well-known BB-94 (batimastat), BB-2516 (marimastat), and BAY12-9566 (tanomastat) [34,202,203]. Unfortunately, in phase III clinical trials, these compounds failed as drugs for the treatment of different types of solid tumours, due to significant dose-limiting musculoskeletal toxicity and/or lack of selectivity for individual MMPs [34,204,205,207]. Later on, more selective MMP2 or MMP9 inhibitors were developed.…”

Section: Mmp2 and Mmp9mentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

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Section: Mmp2 and Mmp9mentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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“…MMP-2, also known as gelatinase A, is known to be expressed in most tissues and cells [49]. It has also been shown to play a key role in the invasion and metastasis of different types of human cancer cells [50][51][52][53][54]. A few studies have found high expression of MMP-2 has in high-grade astrocytic tumors in comparison to normal brain tissue [55,56].…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells

Chung

Hsieh

et al. 2021

Pharmaceuticals

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Glioblastoma multiforme (GBM) is one of the most aggressive and common types of brain tumor. Due to its high proliferation ability, a high lethality rate has been observed with this malignant glial tumor. Terminalia catappa L. (T. catappa) is currently known to have anti-inflammatory and anti-carcinogenesis effects. However, few studies have examined the mechanisms of the leaf extracts of T. catappa (TCE) on GBM cells. In the current study, we demonstrated that TCE can significantly inhibit the migration and invasion capabilities of GBM cell lines without showing biotoxic effects. Matrix metalloproteinases-2 (MMP-2) activity and protein expression were attenuated by reducing the p38 phosphorylation involved in the mitogen-activated protein kinase (MAPK) pathway. By treating with TCE and/or p38 inhibitor (SB203580), we confirmed that p38 MAPK is involved in the inhibition of cell migration. In conclusion, our results demonstrated that TCE inhibits human GBM cell migration and MMP-2 expression by regulating the p38 pathway. These results reveal that TCE contains potent therapeutic compounds which could be applied for treating GBM brain tumors.

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“…Their expression levels are tied to the tumor stage and the patient’s prognosis [ 5 ]. Among MMPs, gelatinases (MMP-2 and -9) have become the focus of many anticancer research programs being validated as druggable targets for halting cancer progression at different stages [ 13 , 14 , 15 , 16 ]. With that, numerous MMPs inhibitors have been introduced over the last decades [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among MMPs, gelatinases (MMP-2 and -9) have become the focus of many anticancer research programs being validated as druggable targets for halting cancer progression at different stages [ 13 , 14 , 15 , 16 ]. With that, numerous MMPs inhibitors have been introduced over the last decades [ 14 , 15 , 16 , 17 ]. Early inhibitors were broad-spectrum mimics of the enzyme’s endogenous ligands capped with the prototypic zinc-binding group hydroxamic acid [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…While these architectures tend to be hydrophobic, some hydrophilic interactions are favored by incorporating amino and carbonyl groups [ 24 , 26 , 27 ]. Accordingly, various lead gelatinases inhibitors were introduced [ 14 , 15 , 16 , 28 ]. In the current study, we tailored triazole-based scaffolds mimicking the general theme of MMPs inhibitors while sparing the hydroxamate moiety with its associated drawbacks.…”

Section: Introductionmentioning

confidence: 99%

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Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation

Albelwi

Teleb

Abu‐Serie

et al. 2021

IJMS

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Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2–5.6-fold) and suppressed cyclin D expression (0.8–0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

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Outline of gelatinase inhibitors as anti-cancer agents: A patent mini-review for 2010-present

Cited by 19 publications

References 85 publications

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells

Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation

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