Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family

Zapico, José María; Pućkowska, Anna; Filipiak, Kamila; Coderch, Claire; Pascual‐Teresa, Beatriz de; Ramos, Ana

doi:10.1039/c4ob01516a

Cited by 16 publications

(22 citation statements)

References 45 publications

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“…High-resolution structures have identified a specific subsite within the MMP catalytic domain termed the S1Ј pocket, and this domain has been exploited in the discovery of several specific inhibitors for MMP-13 (9 -11). A similar approach targeting the S1Ј pocket was utilized to create compounds that had some selectivity for MMP-2 over the closely related MMP-9 (12,13). An alternative approach has targeted the hemopexin domain of membrane type-1 matrix metalloproteinase (MT1-MMP) (14), which is well outside the catalytic domain.…”

Section: Mmpsmentioning

confidence: 99%

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

Scannevin

Alexander

Haarlander

et al. 2017

Journal of Biological Chemistry

113

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Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets. MMPs2 are a family of structurally related zinc-binding proteolytic enzymes that digest extracellular matrix proteins and participate in tissue remodeling and signaling events (1). Currently, ϳ23 MMPs have been identified, comprising secreted and membrane-bound forms, and different family members share some common structural and functional domains and have varying degrees of substrate specificity. Abnormal expression and activation of MMPs has been implicated in the pathogenesis and pathological progression of several different human diseases that are centered in many different tissues in the periphery and central nervous system (2, 3). Initial clinical exploration of synthetic MMP inhibitors was focused on oncology indications, as preventing the breakdown of tissue matrices and barriers was viewed as a potential mechanism to limit tumor metastasis.Despite intensive efforts over many years to develop synthetic MMP inhibitors, only a single MMP inhibitor, Periostat, a tetracycline derivative used in periodontal disease, has progressed into regular clinical use (4). Of the ϳ50 other clinical trials conducted with active site MMP inhibitors, all have failed due to the onset of significant dose-limiting musculoskeletal toxicity ...

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Section: Mmpsmentioning

confidence: 99%

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

Scannevin

Alexander

Haarlander

et al. 2017

Journal of Biological Chemistry

113

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“…Azides 3, 4, and 5, necessary for the click chemistry reactions, were synthesized as described in previous works [ 34 , 35 ] ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Azides 3, 4, and 5, necessary for the click chemistry reactions, were synthesized as described in previous works [34,35] (Figure 3). Triazole-derived alkynes 6a,b were obtained by alkylation of benzotriazole or tetrabromobenzotriazole with 4-bromobut-1-yne in the presence of potassium carbonate.…”

Section: Synthesismentioning

confidence: 99%

“…MS (ESI) m/z 531.0 [M-H] − . (R)-2-(4-(4-(2-(2H-benzo[d][1-3]triazol-2-yl)ethyl)-1H-1,2,3-triazol-1-yl)phenylsulfonamido)-3-phenylpropanoic acid (9b)Method 1A was followed for the click reaction: From (R)-4[34] (110 mg, 0.31 mmol) and 6a (70.7 mg, 0.41 mmol), and after column chromatography (from pure DCM to DCM-MeOH 95:5), compound 9b (85 mg 53%) was obtained as a white solid. m.p.…”

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confidence: 99%

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

Zapico

Acosta

Pastor

et al. 2021

IJMS

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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.

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“…This review summarizes the main achievements in the field of MMPIs imaging probes and constitutes an important contribution to support further research in this area. Our research group has designed, in the last years, highly potent and selective inhibitors of MMP-2, while avoiding other MMPs, including the highly homologous gelatinase MMP-9 [114,115,116,117,118]. The structure based drug design on MMP-13 carried out by the authors has also provided very interesting and highly selective inhibitors [119].…”

Section: Discussionmentioning

confidence: 99%

Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs)

et al. 2019

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Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.

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Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family

Cited by 16 publications

References 45 publications

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

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

Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs)

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