Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Siklos, Marton I.; BenAissa, Manel; Thatcher, Gregory R. J.

doi:10.1016/j.apsb.2015.08.001

Cited by 206 publications

(185 citation statements)

References 208 publications

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“…Cat K and Cat S inhibitors have been tried in clinical trials, with many side effects and little progress (12,13). However, no Cat L inhibitor has been evaluated in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor

Burton

Dougan

Jones

et al. 2017

Molecular and Cellular Biology

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The epithelial mesenchymal transition (EMT) promotes tumor migration and invasion by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers such as vimentin. Cathepsin L (Cat L) is a cysteine protease that can proteolytically activate CCAAT displacement protein/cut homeobox transcription factor (CUX1). We hypothesized that nuclear Cat L may promote EMT via CUX1 and that this could be antagonized with the Cat L-specific inhibitor Z-FY-CHO. Mesenchymal prostate (ARCaP-M and ARCaP-E overexpressing Snail) and breast (MDA-MB-468, MDA-MB-231, and MCF-7 overexpressing Snail) cancer cells expressed lower E-cadherin activity, higher Snail, vimentin, and Cat L activity, and a p110/p90 active CUX1 form, compared to epithelial prostate (ARCaP-E and ARCaP-Neo) and breast (MCF-7 and MCF-7 Neo) cancer cells. There was increased binding of CUX1 to Snail and the E-cadherin promoter in mesenchymal cells compared to epithelial prostate and breast cells. Treatment of mesenchymal cells with the Cat L inhibitor Z-FY-CHO led to nuclear-to-cytoplasmic relocalization of Cat L, decreased binding of CUX1 to Snail and the E-cadherin promoter, reversed EMT, and decreased cell migration/invasion. Overall, our novel data suggest that a positive feedback loop between Snail-nuclear Cat L-CUX1 drives EMT, which can be antagonized by Z-FY-CHO. Therefore, Z-FY-CHO may be an important therapeutic tool to antagonize EMT and cancer progression.KEYWORDS CDP/Cux, EMT, Snail, Z-FY-CHO, cathepsin L P rostate and breast cancers are the leading causes of cancer-related death in men and women, respectively, and metastasis is the primary factor underlying the high mortality rates (1). Proteolytic enzymes that promote invasion and metastasis, such as the lysosomal cysteine protease cathepsin L (Cat L), have been shown to degrade E-cadherin, promoting the epithelial mesenchymal transition (EMT) (2). Furthermore, it has also been shown that silencing Cat L can inhibit transforming growth factor ␤ (TGF-␤)-mediated EMT, cell migration, and invasion by suppressing Snail transcription factor (3). Several recent studies have highlighted an additional unexpected localization and site of action for Cat L within the nucleus in breast, colon, and prostate cancers (4, 5); however, its role in the nucleus is unclear. It was proposed to mediate proteolytic processing of the transcription factor CCAAT displacement protein/cut homeobox transcription factor (CUX1) from the full-length p200 isoform to generate the p110 and p90 isoforms, of which the p110 isoform was shown to act as a cell cycle regulator to

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“…Cat K and Cat S inhibitors have been tried in clinical trials, with many side effects and little progress (12,13). However, no Cat L inhibitor has been evaluated in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor

Burton

Dougan

Jones

et al. 2017

Molecular and Cellular Biology

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“…From studies of peptide aldehydes and other C-terminally modified peptide protease inhibitors, it has become clear that the sidechains in the inhibitor help occupy the P1 and P2 pockets (Siklos et al, 2015) and a free amino terminus can form specific charge contacts in the active site (Katunuma, 2011; Laine and Busch-Petersen, 2010). Thus, side chain identity and N- terminal acylation state are key determinants of selectivity, potentially helping to explain the breadth of chemical diversity in this family.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

Guo

Chang

Wyche

et al. 2017

Cell

190

182

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SUMMARY The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the NIH HMP stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.

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“…Te-SG [33,34]. The difference in Cathepsin inhibition values exhibited by the same compound arise owing to specific features of the various sub-sites in the enzyme which are responsible for the specificity of the protease [35,36]. Thus, in order to design a powerful and specific Cathepsin inhibitor, it is of fundamental importance to have detailed knowledge of the features of each sub-site of each Cathepsin [37][38][39].…”

Section: Decane (1) (3e)-2-chloro-3-(chloromethylidene)-2-(4-methoxymentioning

confidence: 99%

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

Caracelli

Maganhi

Cardoso

et al. 2017

Zeitschrift Für Kristallographie - Crystalline Materials

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Abstract. The molecular structures of the halotelluroxetanes pMeOC6H4Te(X)[C(=C(H)Xꞌ)C(CH2)nO], X = Xꞌ = Cl and n = 6 (1) and X = Cl, Xꞌ = Br and n = 5 (4), show similar binuclear aggregates sustained by { … Te-O}2 cores comprising covalent Te-O and secondary Te⋯O interactions. The resulting C2ClO2(lone-pair) sets define pseudo-octahedral geometries. In each structure, C-X⋯(arene) interactions lead to supramolecular layers. Literature studies have shown these and related compounds (i.e. 2: X = Xꞌ = Cl and n = 5; 3: X = Xꞌ = Br and n = 5) to inhibit Cathepsins B, K, L and S to varying extents. Molecular docking calculations have been conducted on ligands (i.e. cations derived by removal of the telluriumbound X atoms) 1ꞌ-3ꞌ (note 3ꞌ = 4ꞌ) enabling correlations between affinity for sub-sites and inhibition. The common feature of all docked complexes was the formation of a Te-S covalent bond with cysteine residues, the relative stability of the ligands with an E-configuration and the formation of a C-O … π interaction with the phenyl ring; for 1ꞌ the Te-S covalent bond was weak, a result correlating with its low inhibition profile. At the next level differences are apparent, especially with respect to the interactions formed by the organic-ligand-bound halides.

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Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Cited by 206 publications

References 208 publications

Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor

Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor

Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

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