Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors

Dublanchet, Anne‐Claude; Ducrot, Pierre; Andrianjara, Charles R.; O’Gara, Margaret; Morales, Renaud; Compère, Delphine; Denis, Alexis; Blais, Stéphane; Cluzeau, Philippe; Courté, Karine; Hamon, Jacques; Moreau, F.; Prunet, Marie-Laure; Tertre, Anita

doi:10.1016/j.bmcl.2005.05.079

Cited by 66 publications

(33 citation statements)

References 11 publications

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“…To the best of our knowledge, compounds 1 and 2 are the first examples of highly potent and selective MMP-12 inhibitors (42)(43)(44). Several studies have assessed the functional role of MMP-12 in different diseases, using MMP-12-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

Devel

Rogakos

David

et al. 2006

Journal of Biological Chemistry

141

154

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The matrix metalloproteinases (MMPs)2 form a group of structurally related extracellular zinc endoproteases able to degrade at least one protein component of the extracellular matrix (1). Based on this property, MMPs are considered to be critical mediators of both normal and pathological tissue remodeling processes (2, 3). Their overexpression is observed in and associated with a variety of diseases, including cancer (4, 5), arthritis (6), multiple sclerosis (7,8), and atherosclerosis (9, 10). Therefore, there is substantial interest in developing MMP synthetic inhibitors for a variety of therapeutic indications (11)(12)(13)(14)(15). Results of the first clinical trials with broad spectrum MMP inhibitors in cancer therapy were disappointing, highlighting the need for better understanding of the exact role of each MMP during the different stages of tumor progression (16). Recent research in this field has focused on the development of inhibitors that fully differentiate one MMP from another (17). This is a particularly difficult task, since the topology and nature of the residues in the enzyme's active site are highly conserved among the different MMPs (18). Moreover, parts of the MMP catalytic domain, which play a critical role in enzyme specificity, seem to be highly flexible (19,20). This situation may explain why most previously reported MMP synthetic inhibitors preferentially inhibit some MMPs but are not exclusive inhibitors of a single MMP. A recent breakthrough in this field was achieved by identifying the first highly selective synthetic inhibitor of MMP-13 (21). Selective inhibitors for MMP-2 and MMP-9 have also been reported recently, but their degree of selectivity toward MMPs is less than that achieved for the MMP-13-selective inhibitor (22).To identify highly selective MMP inhibitors, libraries of phosphinic peptides were prepared. Phosphinic peptides are good transition state mimics and have been shown to behave as highly potent inhibitors of different zinc metalloproteinases (23). To probe the SЈ 1 cavity of MMPs, a chemical strategy that makes it possible to prepare phosphinic peptides harboring various substituents in their PЈ 1 position was used (see Scheme 1). This strategy relies on the use of a common precursor, which can be modified in one step, to prepare phosphinic peptides displaying substituted isoxazole side chains in their PЈ 1 position (24). In such phosphinic peptides, the isoxazole ring is used as a rigid scaffold to project in the right orientation various chemical groups able to interact with the SЈ 1 subsite of MMPs, which corresponds to a deep cavity. Based on this strategy, four libraries of phosphinic peptides, containing four different isoxazole side chains in their PЈ 1 position, were prepared by introducing additional chemical diversity in the PЈ 2 and PЈ 3 positions of the inhibitors (see Scheme 1). Screening of these libraries against 10 different MMPs allowed us to identify highly selective inhibitors of MMP-12. Based on the unique structure of these inhibitors, a highl...

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Section: Discussionmentioning

confidence: 99%

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

Devel

Rogakos

David

et al. 2006

Journal of Biological Chemistry

141

154

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“…So, MMPIs optimised to spare either of these MMP antitargets might spare the other. The development of novel specific inhibitors for MMP12 (Dublanchet et al, 2005) and MMP13 was attributed to differences in the S 1 0 pocket. An additional small region termed the 'S 1 0 side-pocket' or S 1 0 * was used for specifically targeting MMP13 .…”

Section: Smentioning

confidence: 99%

“…A high throughput screen aimed to find non-zinc chelating compounds that showed additive inhibition against MMP12 over that achieved in the presence of a hydroxamate inhibitor alone (Dublanchet et al, 2005). Two nonpeptidic non-zinc chelating inhibitors in the S 1 0 pocket were found that could be crystallised in the presence of an acetohydroxamate anion that bound the active site Zn 2 þ ion (Morales et al, 2004).…”

Section: Exosite Binding and Allosteric Inhibitorsmentioning

confidence: 99%

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

2006

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The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection.

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“…Pfizer identified a biphenyl(thienyl) derivative (compound 1, Figure 1B) which inhibited potently MMP-12 and -13 with modest selectivity over MMP-2, -3, -8 and -9 8,9 . Although it contains another potential ZBG, a carboxylic group, the crystal structure of 1 with MMP-12 revealed that this inhibitor partially occupies the deep S1…”

Section: Introductionmentioning

confidence: 99%

Kinetic characterization of 4,4′-biphenylsulfonamides as selective non-zinc binding MMP inhibitors

Santamaria

Nuti

Cercignani

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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We describe the characterisation of a series of 4,4 0 -biphenylsulfonamides as selective inhibitors of matrix metalloproteases MMP-2 and -13, two enzymes involved in cell invasion and angiogenesis. Double-inhibitor studies in the presence of acetohydroxamic acid show that these molecules do not bind the catalytic zinc. Moreover, two of the characterised inhibitors (11 and 19) act as non-competitive inhibitors, whereas the para-methyl ester derivative 13 behaves as a competitive inhibitor. This finding suggests that this class of molecules binds to a catalytic subsite, possibly the S1 0 -pocket. Moreover, since these compounds also act as inhibitors of carbonic anhydrases (CAs), another family of enzymes involved in cell invasion, they could be potentially useful as CA/MMP dual target inhibitors with increased efficacy as anticancer agents.

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Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors

Cited by 66 publications

References 11 publications

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

Kinetic characterization of 4,4′-biphenylsulfonamides as selective non-zinc binding MMP inhibitors

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