TNP-470

Milkowski, Deborah M.; Weiss, Rachelle A.

doi:10.1385/0-89603-641-3:385

Cited by 4 publications

(3 citation statements)

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“…However, this distinction is clearly of interest since MetAP2 has been defined as the target of the fumagillan class of natural product inhibitors that potently abrogate the angiogenesis process. , MetAP2 is pharmacologically linked to cytostatic growth arrest at the G 1 /S phase of the cell cycle in vascular endothelial cells and some tumor lines, with minimal effect on most primary cells of nonendothelial type . TNP-470, a synthetic fumagillan analog with higher potency and lower toxicity has entered clinical trials for various cancers . However, dose limiting cerebellar toxicity was reported for this covalent inhibitor. , MetAP2-specific reversible inhibitors, including A-357300 and an anthranilic acid sulfonamide (A-800141), have demonstrated activity in animal models of angiogenesis and tumor growth. , In addition, a nonselective MetAP inhibitor (LAF-389) has also shown efficacy in preclinical animal models .…”

Section: Introductionmentioning

confidence: 99%

Discovery, Identification, and Characterization of Candidate Pharmacodynamic Markers of Methionine Aminopeptidase-2 Inhibition

et al. 2008

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The catalytic activity of methionine aminopeptidase-2 (MetAP2) has been pharmacologically linked to cell growth, angiogenesis, and tumor progression, making this an attractive target for cancer therapy. An assay for monitoring specific protein changes in response to MetAP2 inhibition, allowing pharmacokinetic (PK)/pharmacodynamic (PD) models to be established, could dramatically improve clinical decision-making. Candidate MetAP2-specific protein substrates were discovered from undigested cell culture-derived proteomes by MALDI-/SELDI-MS profiling and a biochemical method using (35)S-Met labeled protein lysates. Substrates were identified either as intact proteins by FT-ICR-MS or applying in-gel protease digestions followed by LC-MS/MS. The combination of these approaches led to the discovery of novel MetAP2-specific substrates including thioredoxin-1 (Trx-1), SH3 binding glutamic acid rich-like protein (SH3BGRL), and eukaryotic elongation factor-2 (eEF2). These studies also confirmed glyceraldehye 3-phosphate dehydrogenase (GAPDH) and cyclophillin A (CypA) as MetAP2 substrates. Additional data in support of these proteins as MetAP2-specific substrates were provided by in vitro MetAP1/MetAP2 enzyme assays with the corresponding N-terminal derived peptides and 1D/2D Western analyses of cellular and tissue lysates. FT-ICR-MS characterization of all intact species of the 18 kDa substrate, CypA, enabled a SELDI-MS cell-based assay to be developed for correlating N-terminal processing and inhibition of proliferation. The MetAP2-specific protein substrates discovered in this study have diverse properties that should facilitate the development of reagents for testing in preclinical and clinical environments.

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Section: Introductionmentioning

confidence: 99%

Discovery, Identification, and Characterization of Candidate Pharmacodynamic Markers of Methionine Aminopeptidase-2 Inhibition

et al. 2008

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“…This inhibition of the MetAP-2 enzyme activity provides the molecular link that triggers the in vitro growth arrest of human umbilical vein endothelial cells (HUVEC) in the late G 1 phase of the cell cycle (20,21). Fumagillin class compounds have also been proven to be potent angiogenesis inhibitors in vivo, and TNP-470 has advanced into human clinical trials for several oncology indications (22).…”

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confidence: 99%

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

Bernier

Lazarus

Clark

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

118

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The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI 50) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI 50, 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan-polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent antiproliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan-polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.

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“…TNP-470 showed significant inhibition of tumors in clinical trials, including durable complete regression. 19 The clinical utility of TNP-470, however, was limited by neurotoxicity. This side effect was overcome when Satchi-Fainaro et al 20 in the Folkman lab conjugated TNP-470 to N-(2-hydroxypropyl)methacrylamide to form caplostatin.…”

mentioning

confidence: 99%

The history of angiogenesis inhibitors

Ribatti

2007

Leukemia

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TNP-470

Cited by 4 publications

References 0 publications

Discovery, Identification, and Characterization of Candidate Pharmacodynamic Markers of Methionine Aminopeptidase-2 Inhibition

Discovery, Identification, and Characterization of Candidate Pharmacodynamic Markers of Methionine Aminopeptidase-2 Inhibition

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

The history of angiogenesis inhibitors

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