Bioactive conformation of a potent stromelysin inhibitor determined by X-nucleus filtered and multidimensional NMR spectroscopy

Gonnella, Nina C.; Li, Yu-Chin; Zhang, Xiaolu; Paris, Christine

doi:10.1016/s0968-0896(97)00173-9

Cited by 47 publications

(49 citation statements)

References 32 publications

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“…The non-peptidic inhibitors, whose structures were determined in complex with various MMPs, were either sulfonamides, phosphinamides or sulfones with hydroxamic acid or carboxylate zinc-binding functions [59,68,69,78,79]. The first reported structure of a non-peptidic sulfonamide hydoxamic acid inhibitor was CGS 27023A (17; see Table 8 below) in complex with MMP-3 [59,93], Fig. (6).…”

Section: Right Side (Primed) Inhibitor Bindingmentioning

confidence: 99%

“…A para-(biphenyl)ethyl moiety is positioned to allow deep penetration into the S 1ṕ ocket. The mode of binding of CGS 27023A (17) to MMP-3 as well as the full 3-dimensional solution structure of the catalytic domain of MMP-3 complexed with CGS 27023A have been determined by NMR spectroscopy [59,93,140,141]. The para-methoxyphenyl substituent occupies, but does not fill, the S 1´ specificity pocket while the isopropyl and pyridylmethyl substituents occupy the S 1 and S 2ś ubsites, respectively.…”

Section: Succinate Peptidomimetic Inhibitors Of Mmpsmentioning

confidence: 99%

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The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

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Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

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Section: Right Side (Primed) Inhibitor Bindingmentioning

confidence: 99%

Section: Succinate Peptidomimetic Inhibitors Of Mmpsmentioning

confidence: 99%

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

View full text Add to dashboard Cite

show abstract

“…The characteristic broad spectrum may correlate to its larger structure, which accommodates the S' 1 pocket of MMP-3 (3,8,9). Since the S' 1 pocket of gelatinase is deeper than that of MMP-3, we designed a backbone of hydroxyproline linked with the longer and flexible caffeoyl group to extend into the deeper S' 1 pocket (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, regulation of gelatinases is crucial in inhibiting tumor invasion and metastasis. Three-dimensional structural analyses of MMP molecules showed that the S' 1 active pocket in MMP-2 and -9 is deeper than that of other types of MMPs such as MMP-3 (3)(4)(5)(6). This property provides a helpful clue for constructing gelatinase-specific inhibitors via structure-based design strategies.…”

Section: Introductionmentioning

confidence: 95%

Using caffeoyl pyrrolidine derivative LY52, a potential inhibitor of matrix metalloproteinase-2, to suppress tumor invasion and metastasis

Yuan²,

Tian³

et al. 2006

Int J Mol Med

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Abstract. LY52 is a caffeoyl pyrrolidine derivative designed to fit the S' 1 active pocket of gelatinases that act in tumor invasion and metastasis. Herein, we examined the effects of LY52 on expression of matrix metalloproteinase (MMP)-2 expression in human breast cancer MDA-MB-231 cells and on in vitro invasion and in vivo metastasis. LY52 significantly blocked MMP-2 activity as evidenced by a decrease in the degradation of succinylated gelatin. Gelatin zymography analysis showed that LY52 (0.1-200 μg/ml) inhibited expression of active MMP-2 in concanavalin A-stimulated MDA-MB-231 cells. Inhibition of MMP-2 expression was also observed in tissue of tumor xenografts in mice that were orally administered LY52 (25 or 100 mg/kg). Furthermore, LY52 displayed an inhibitory effect on in vitro invasion of MDA-MB-231 cells and pulmonary metastasis of B16F10 murine melanoma cells in mice without significant toxic effects. These results suggest that LY52 is a potential MMP-2 inhibitor that may effectively suppress tumor invasion and metastasis.

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“…They are structure-based inhibitors designed by means of x-ray crystallography. They show selective inhibitory activity against the various MMPs on the basis of the difference in size and shape of the S1' pocket (31). Moreover, non-hydroxamic acid pseudopeptides or non-peptidic MMP inhibitors have been discovered in recent years and studied in preclinical models.…”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

MMP Inhibitors: Experimental and Clinical Studies

1999

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MATRIX METALLOPROTEASESMatrix metalloproteases (MMPs) are a family of zinc-dependent secreted or transmembrane proteins which degrade extracellular matrix components under physiological and pathological conditions (1, 2). Their main structural and functional similarities are a) a catalytic domain characterized by an HEXGH motif and the presence of a zinc atom essential for the proteolytic activity; b) a propeptide in the aminoterminal region, characterized by the PRCGVPD sequence responsible for latency in zymogens. Additional domains are characteristic of the different subfamilies of MMPs and contribute to substrate specificity, inhibitor binding, matrix binding and cell-surface localization. MMPs can be divided into three major subgroups on the basis of their substrate target: collagenases, which degrade fibrillar collagen; gelatinases, which degrade denatured and basement membrane collagens and stromelysins, which degrade proteoglycans and glycoproteins. An additional group, the transmembrane domain family (MTMMPs), is the most recently discovered class of MMPs. The members of this family contain a sequence spanning the cellular membrane and are involved in the proteolytic activation of other MMPs (3). Physiological inhibitors of MMPsThe catalytic activity of the MMPs is regulated at multiple levels including transcription, secretion, activation of the proenzyme and function of the activated enzyme. The messenger RNA of MMPs is transcriptionally regulated by growth factors, cytokines, hormones, oncogenes and tumor promoters (4-7). mRNA stability and translation are also regulated (8,9). MMPs are synthesized in a latent form which needs to be activated by proteolytic cleavage by other enzymes; activation is thus another way to regulate the amount of active MMPs. A final level of regulation is the inhibition of MMP activity by non-specific (α2-macroglobulin) or specific inhibitors, the tissue inhibitors of MMPs (TIMP-1, TIMP-2, TIMP-3 and TIMP-4) (10).TIMPs bind non-covalently to the catalytic domain of MMPs, thereby inhibiting their activity. It has also been shown that TIMP-2 forms a trimolecular complex with MT1-MMP and pro-MMP2 on the cell surface and regulates the formation of mature MMP-2 (11).The International Journal of Biological Markers / Vol. 14 no. 4, pp. 232-238 © Wichtig Editore, 1999

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Bioactive conformation of a potent stromelysin inhibitor determined by X-nucleus filtered and multidimensional NMR spectroscopy

Cited by 47 publications

References 32 publications

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Using caffeoyl pyrrolidine derivative LY52, a potential inhibitor of matrix metalloproteinase-2, to suppress tumor invasion and metastasis

MMP Inhibitors: Experimental and Clinical Studies

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