Design, Synthesis, and Evaluation of In Vivo Potency and Selectivity of Epoxysuccinyl-Based Inhibitors of Papain-Family Cysteine Proteases

Sadaghiani, Amir Masoud; Verhelst, Steven H. L.; Gocheva, Vasilena; Hill, Kimberly D.; Majerová, Eva; Stinson, Sherman F.; Joyce, Johanna A.; Bogyo, Matthew

doi:10.1016/j.chembiol.2007.03.010

Cited by 67 publications

(66 citation statements)

References 29 publications

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“…4). The treatment of U-937 Mfs with CtsBspecific CA-074 [32], CtsX-specific AMS-36, CtsB-, and CtsXspecific AMS-30 [33] inhibitors and the CtsS-specific inhibitor LHVS [34] strongly attenuated the extracellular degradation of DQ-collagen IV. Notably, this process was not affected by the broad-spectrum MMP inhibitor Batimastat, suggesting that MMPs are not crucial for extracellular collagenolytic activity during 3D invasion of human Mfs.…”

Section: Ecm Degradation Of Human Mfs Is Mediated By Cysteine Cathepsinsmentioning

confidence: 99%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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IntroductionThe ability of macrophages (Mfs) to progress to specific tissues, increase matrix remodeling, and induce angiogenesis is essential for their normal physiological function [1,2]. In addition, tissue infiltration of Mfs is also involved in pathological processes such as chronic inflammation, atherosclerosis, neurodegenerative disorders, and cancer progression [3]. The presence of Mfs Correspondence: Dr. Bojana Mirković e-mail: bojana.mirkovic@ffa.uni-lj.si within tumors is generally a marker of poor prognosis since they enhance angiogenesis and metastasis [4]. Furthermore, tumorassociated Mfs are emerging as essential matrix-remodeling cells during tumor-cell invasion. They have been reported to be present at high frequency at the invasive front of the tumor, where the breakdown of extracellular matrix (ECM) occurs [5]. Therefore, there is a great need to specifically control tissue infiltration of Mfs by targeting Mf migration-related molecules [6]. * These authors contributed equally to the present work. Eur. J. Immunol. 2012. 42: 3429-3441 Mf migration has been studied extensively in two dimensions (2D) on artificial substrates; however, in vivo Mfs migrate through physiological and pathological tissue and interact with the surrounding three-dimensional (3D) ECM, including basement membrane, collagen-rich interstitial matrices, and dense tissues such as tumors. Cells of different origins and/or at different differentiation stages use distinct mechanisms of cell motility in the 3D environment. In the mesenchymal mode, cells wider than the matrix pore size degrade the matrix via proteolytic and force-based matrix remodeling, thus migrating in a "path-generating" manner, while amoeboid cells squeeze through pre-existing pores in a proteaseindependent fashion in a "path-finding" mode [7,8]. The first 3D migration studies performed on cells of the immune system suggested that these cells migrate in a protease-independent fashion [7,9]. In contrast, a recent study demonstrated that Mfs adapt their migration strategy depending on the architecture of the 3D environment. In this study, Mfs were found to use the amoeboid migration mode in fibrillar collagen I and the mesenchymal migration mode in dense substrates, such as Matrigel and gelled collagen I [10].The invasion of cancer cells is facilitated by ECM-degrading invadopodia [11]. Podosomes are structures functionally similar to the invadopodia that are found in Mfs, osteoclasts, and DCs [12,13]. During migration on 2D surfaces [14], dot or ringlike podosomes form at the ventral surface of the migrating cells where they establish direct contact with the substratum and are also involved in matrix degradation [11]. Structurally, podosomes comprise a concentrated core of F-actin and actin-regulatory proteins [14]. Surrounding the core is a ring region that contains scaffolding-, signaling-, and integrin-binding proteins, including the typical focal adhesion proteins vinculin, talin, paxillin, and FAK [15]. When Mfs migrate in a 3D environment (i.e., migra...

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Section: Ecm Degradation Of Human Mfs Is Mediated By Cysteine Cathepsinsmentioning

confidence: 99%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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“…The cathepsin-specific ABP DCG-04 has been applied to the evaluation of cathepsin inhibitors in RIP1-TAG2 transgenic mice, a mouse model of pancreatic cancer [42,43]. In these studies, inhibitors were injected into mice, and normal and tumor tissue samples were collected and analyzed for residual cathepsin activity.…”

Section: Enzyme Inhibitor Discovery and Verificationmentioning

confidence: 99%

“…Importantly, fluorescently-labeled DCG-04 enabled the biochemical identification and monitoring of the cysteine cathepsins during tumorigenesis in these mice. In a follow-up study, a panel of cathepsin inhibitors was evaluated in these mice using radiolabeled DCG-04 [42]. Inhibitors were optimized for selectivity and potency based on these results and then were reprofiled in vivo.…”

Section: Enzyme Inhibitor Discovery and Verificationmentioning

confidence: 99%

Application of activity-based probes to the study of enzymes involved in cancer progression

Paulick

Bogyo

2008

Current Opinion in Genetics & Development

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SummaryMany tumor cells have elevated levels of hydrolytic and proteolytic enzymes, presumably to aid in key processes such as angiogenesis, cancer cell invasion, and metastasis. Since the activities of these enzymes are often regulated by post-translational mechanisms, their functional roles in cancer progression are difficult to study using traditional genomic and proteomic methods. Thus, methods that allow for the direct monitoring of enzyme activity in a physiologically relevant environment are required to better understand the roles of specific players in the complex process of tumorigenesis. This review highlights advances in the field of activity-based proteomics, which uses small molecules known as activity-based probes (ABPs) that covalently bind to the catalytic site of target enzymes. We discuss the application of ABPs to cancer biology, specifically to the discovery of tumor biomarkers, the screening of enzyme inhibitors, and the imaging of enzymes implicated in cancer.

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“…Previously Watanabe et al reported the synthesis of a R 1 derivative with oxygen atom substitutes as an inhibitor of epoxysuccinyl-peptide cathepsin B inhibitor, 13) Sadaghiani et al also synthesized a similar epoxysuccinyl-peptide cathepsin B inhibitor with a phenyl group at the R 1 position. 9) Both molecules however failed to maintain the overall inhibition and selectivity to Cathepsin B. Here we successfully synthesized a series of E64d derivatives with Methionine (Met, contains sulfur) substitute at R 1 position.…”

mentioning

confidence: 99%

“…1). 9) Both are derivatives of the epoxysuccinyl-peptide and readily bind to the S 1 ′-S 2 ′ subsites of cathepsin B as highly selective inhibitors. 10,11) The selectivity of E64d and its related analogs has been determined to be due to efficient hydrogen-bond interactions between a free carboxylic acid on the inhibitor and two histidine residues in the occluding loop structure found in cathepsin B.…”

mentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationship Study of Epoxysuccinyl–Peptide Derivatives as Cathepsin B Inhibitors

Zhang

Yang

Wang

et al. 2017

Biological & Pharmaceutical Bulletin

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Cathepsin B is a lysosomal cysteine protease involved in many diseases. The present research demonstrates that derivatives of epoxysuccinyl-peptide are effective and selective cathepsin B inhibitors. We synthesized a series of epoxysuccinyl-peptide derivatives based on the well-known cathepsin B inhibitor E64d. Specifically, we substituted the 2-methylpropane group at the R 1 position of E64d with a sulfane, such as ethyl(methyl) sulfane or benzyl(methyl) sulfane. We also designed and synthesized a library of molecules with various substituents at the R 2 position of E64d to replace 2-methylbutane. By studying the structure-activity relationships of these newly synthesized molecules as cathepsin B inhibitors, we demonstrated that substituting ethyl(methyl) sulfane for 2-methylbutane (R 2 ) of E64d improves the inhibitory activity and selectivity for cathepsin B inhibition. Our new cathepsin B inhibitors were highly effective and selective.

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Design, Synthesis, and Evaluation of In Vivo Potency and Selectivity of Epoxysuccinyl-Based Inhibitors of Papain-Family Cysteine Proteases

Cited by 67 publications

References 29 publications

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Application of activity-based probes to the study of enzymes involved in cancer progression

Design, Synthesis, and Structure–Activity Relationship Study of Epoxysuccinyl–Peptide Derivatives as Cathepsin B Inhibitors

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