Matrix metalloproteinase9 as the protein target in anti-breast cancer drug discovery: an approach by targeting hemopexin domain

Adhipandito, Christophorus Fideluno; Ludji, Diana Putri Kartika Sari; Aprilianto, Eko; Jenie, Riris Istighfari; Al-Najjar, Belal O.; Hariono, Maywan

doi:10.1186/s43094-019-0001-1

Cited by 25 publications

(10 citation statements)

References 101 publications

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“…However, since the target sites share high similarity among MMP family members [ 43 , 44 ] and since other MMP domains and interacting molecules also affect MMP biological activity [ 12 , 61 , 63–65 ], no real progress has been reported in this endeavor. Our strategy for selective and efficient inhibition of the biological activity of MMP9 therefore focused on the three-pronged targeting of: (i) the catalytic domain of MMP9, (ii) the specific interactions between the PEX domain of MMP9, which shares low similarity within the PEX domains of all other MMP family members [ 66 ], and CD44, a receptor that is co-localized with and is functionally related to MMP9 [ 8 , 12 , 13 ], and (iii) the specific interactions between the PEX domain of one MMP9 monomer with the same PEX domain of a different MMP9 monomer to inhibit homodimerization of MMP9 via its PEX domains.…”

Section: Discussionmentioning

confidence: 99%

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Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy

Yosef

Hayun

Papo

2021

Biochemical Journal

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Crosstalk of the oncogenic matrix metalloproteinase-9 (MMP9) and one of its ligands, CD44, involves cleavage of CD44 by the MMP9 catalytic domain, with the CD44–MMP9 interaction on the cell surface taking place through the MMP9 hemopexin domain (PEX). This interaction promotes cancer cell migration and invasiveness. In concert, MMP9-processed CD44 induces the expression of MMP9, which degrades ECM components and facilitates growth factor release and activation, cancer cell invasiveness, and metastasis. Since both MMP9 and CD44 contribute to cancer progression, we have developed a new strategy to fully block this neoplastic process by engineering a multi-specific inhibitor that simultaneously targets CD44 and both the catalytic and PEX domains of MMP9. Using a yeast surface display technology, we first obtained a high-affinity inhibitor for the MMP9 catalytic domain, which we termed C9, by modifying a natural non-specific MMP inhibitor, N-TIMP2. We then conjugated C9 via a flexible linker to PEX, thereby creating a multi-specific inhibitor (C9-PEX) that simultaneously targets the MMP9 catalytic and PEX domains and CD44. It is likely that, via its co-localization with CD44, C9-PEX may compete with MMP9 localization on the cell surface, thereby inhibiting MMP9 catalytic activity, reducing MMP9 cellular levels, interfering with MMP9 homodimerization, and reducing the activation of downstream MAPK/ERK pathway signaling. The developed platform could be extended to other oncogenic MMPs as well as to other important target proteins, thereby offering great promise for creating novel multi-specific therapeutics for cancer and other diseases.

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Section: Discussionmentioning

confidence: 99%

“…reduction in CD44 cleavage by MMP9 [ 14 ]). Although MMP9 is a soluble protein [ 68 ], it can be localized on the cell surface through its binding to CD44 [ 12 , 66 ]. When MMP9 is localized on the cell surface, it might not be available for inhibition by TIMP, as previously shown for TIMP1 [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy

Yosef

Hayun

Papo

2021

Biochemical Journal

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“…Furthermore, the extract also actively inhibited the proliferation of 4T1 metastatic breast cancer cells. All Ageratum samples could be suggested to prevent the peptide substrate binding in the catalytic site of MMP9 by interrupting the homodimerization of PEX9 [ 17 ]. However, further investigation is still warranted to confirm the activity of the extract on the cell migration assay.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, an alternative mechanism for targeting MMP9 in which the catalytic zinc is not targeted has been proposed to overcome the selectivity issue [ 16 ]. Example of such an alternative is targeting the hemopexin-like domain (PEX9) of MMP9 instead of the catalytic domain [ 17 ]. PEX9 contains non-conserved amino acid residues in its binding pocket [ 18 ] and is located next to the catalytic site [ 19 ], thus targeting PEX9 might offer as a good strategy for the development of selective inhibitors for the cancer treatment [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study

et al. 2020

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Matrix metalloproteinase9 (MMP9) is known to be highly expressed during metastatic cancer where most known potential inhibitors failed in the clinical trials. This study aims to select local plants in our state, as anti-breast cancer agent with hemopexin-like domain of MMP9 (PEX9) as the selective protein target. In silico screening for PEX9 inhibitors was performed from our in house-natural compound database to identify the plants. The selected plants were extracted using methanol and then a step-by-step in vitro screening against MMP9 was performed from its crude extract, partitions until fractions using FRET-based assay. The partitions were obtained by performing liquid–liquid extraction on the methanol extract using n-hexane, ethylacetate, n-butanol, and water representing nonpolar to polar solvents. The fractions were made from the selected partition, which demonstrated the best inhibition percentage toward MMP9, using column chromatography. Of the 200 compounds screened, 20 compounds that scored the binding affinity −11.2 to −8.1 kcal/mol toward PEX9 were selected as top hits. The binding of these hits were thoroughly investigated and linked to the plants which they were reported to be isolated from. Six of the eight crude extracts demonstrated inhibition toward MMP9 with the IC50 24 to 823 µg/mL. The partitions (1 mg/mL) of Ageratum conyzoides aerial parts and Ixora coccinea leaves showed inhibition 94% and 96%, whereas their fractions showed IC50 43 and 116 µg/mL, respectively toward MMP9. Using MTT assay, the crude extract of Ageratum exhibited IC50 22 and 229 µg/mL against 4T1 and T47D cell proliferations, respectively with a high safety index concluding its potential anti-breast cancer from herbal.

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“…The high expression of the matrix metalloproteinase9 (MMP9) protein is one of the indicators during diagnosis [ 4 , 5 ]. Although drug discovery targeting this protein is desirable, a potent MMP9 inhibitor is usually limited by its adverse reaction to drugs, such as musculoskeletal syndromes [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study (Part II)

et al. 2021

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In our previous work, the partitions (1 mg/mL) of Ageratum conyzoides (AC) aerial parts and Ixora coccinea (IC) leaves showed inhibitions of 94% and 96%, respectively, whereas their fractions showed IC50 43 and 116 µg/mL, respectively, toward Matrix Metalloproteinase9 (MMP9), an enzyme that catalyzes a proteolysis of extracellular matrix. In this present study, we performed IC50 determinations for AC n-hexane, IC n-hexane, and IC ethylacetate partitions, followed by the cytotoxicity study of individual partitions against MDA-MB-231, 4T1, T47D, MCF7, and Vero cell lines. Successive fractionations from AC n-hexane and IC ethylacetate partitions led to the isolation of two compounds, oxytetracycline (OTC) and dioctyl phthalate (DOP). The result showed that AC n-hexane, IC n-hexane, and IC ethylacetate partitions inhibit MMP9 with their respective IC50 as follows: 246.1 µg/mL, 5.66 µg/mL, and 2.75 × 10−2 µg/mL. Toward MDA-MB-231, 4T1, T47D, and MCF7, AC n-hexane demonstrated IC50 2.05, 265, 109.70, and 2.11 µg/mL, respectively, whereas IC ethylacetate showed IC50 1.92, 57.5, 371.5, and 2.01 µg/mL, respectively. The inhibitions toward MMP9 by OTC were indicated by its IC50 18.69 µM, whereas DOP was inactive. A molecular docking study suggested that OTC prefers to bind to PEX9 rather than its catalytic domain. Against 4T1, OTC showed inhibition with IC50 414.20 µM. In conclusion, this study furtherly supports the previous finding that AC and IC are two herbals with potential to be developed as triple-negative anti-breast cancer agents.

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Matrix metalloproteinase9 as the protein target in anti-breast cancer drug discovery: an approach by targeting hemopexin domain

Cited by 25 publications

References 101 publications

Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy

Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study (Part II)

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