Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates

Heinrich, Timo; Buchstaller, Hans‐Peter; Cezanne, Bertram; Rohdich, Felix; Bomke, Jörg; Friese-Hamim, Manja; Krier, Mireille; Knöchel, Thorsten; Müsil, Djordje; Leuthner, Birgitta; Zenke, Frank T.

doi:10.1016/j.bmcl.2016.12.019

Cited by 24 publications

(23 citation statements)

References 25 publications

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“…Taken together, the crystallographic data suggest the Tp Ph,Me Zn(MBI) model complex is a useful evaluative tool for metal binding, and may be useful to recapitulate coordination behaviour of similar substitutions in metalloenzyme inhibitors. 22 To further understand the electronic effect of each bioisostere replacement, the physicochemical properties of the MBIs were measured.…”

Section: Synthesis and Characterization Of Model Complexesmentioning

confidence: 99%

Effect of heterocycle content on metal binding isostere coordination

2020

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Section: Synthesis and Characterization Of Model Complexesmentioning

confidence: 99%

Effect of heterocycle content on metal binding isostere coordination

2020

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“…Another HTS campaign was reported where elaborated purines were identified as Mn-hMetAP2 inhibitors. 732 The lead purine compound achieved a modest gain (<10-fold) in activity, with attachment of a 5-isoquinoline being the most active (MetAPi-9, IC 50 = 230 nM, Figure 77). Elaboration of the purine with even a methyl group resulted in decreased activity.…”

Section: Peptidases (Ec 34)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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“…TNP470 is a synthetic analog of fumagillin, which has been shown to inhibit tumor growth in several clinical trials 49 . TNP470 blocks non-canonical Wnt signaling by targeting methionine aminopeptidase-2, a cytoplasmic metalloenzyme responsible for removing the N-terminal methionine from nascent proteins 50 . Intravitreal injection of TNP470 reduced neovascular growth in OIR retinas but did not promote revascularization of the central retina.…”

Section: Discussionmentioning

confidence: 99%

Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy

Lee

Elaskandrany

Lau

et al. 2017

Sci Rep

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CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization. This is consistent with the role of CCN1 as a negative feedback regulator of vascular endothelial growth factor (VEGF) receptor activation. In the mouse model of oxygen-induced retinopathy (OIR), pericytes become the predominant CCN1 producing cells. Pericyte-specific deletion of CCN1 significantly decreases pathological retinal neovascularization following OIR. CCN1 induces the expression of the non-canonical Wnt5a in pericyte but not in EC cultures. In turn, exogenous Wnt5a inhibits CCN1 gene expression, induces EC proliferation and increases hypersprouting. Concordantly, treatment of mice with TNP470, a non-canonical Wnt5a inhibitor, reestablishes endothelial expression of CCN1 and significantly decreases pathological neovascular growth in OIR. Our data highlight the significance of CCN1-EC and CCN1-pericyte communication signals in driving physiological and pathological angiogenesis.

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Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates

Cited by 24 publications

References 25 publications

Effect of heterocycle content on metal binding isostere coordination

Effect of heterocycle content on metal binding isostere coordination

Targeting Metalloenzymes for Therapeutic Intervention

Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy

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