TNP-470

Milkowski, Deborah M.; Weiss, Rachelle A.

doi:10.1007/978-1-59259-453-5_22

Cited by 6 publications

(2 citation statements)

References 21 publications

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“…Fumagillin was found by Don Ingber in the Folkman lab to inhibit endothelial cell proliferation without causing endothelial cell apoptosis, when a tissue culture plate of endothelial cells became contaminated with a fungus, Aspergillus fumigatus fresenius (27,49). Scientists at Takeda Chemical Industries (Osaka, Japan) made a synthetic analogue of fumagillin called TNP-470, which, as mentioned 7 above, inhibits endothelial proliferation in vitro at a concentration 3 logs lower than the concentration necessary to inhibit fibroblasts and tumor cells.…”

Section: Caplostatinmentioning

confidence: 99%

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Angiogenesis

2006

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Angiogenesis inhibitors for the treatment of cancer have now been approved by the Food and Drug Administration in the United States, and in 28 other countries including China. Clinical application of this new class of drugs is informed by certain principles from angiogenesis research. Oncogenic mutations initiate tumorigenesis, but angiogenesis is necessary for expansion of tumor mass. Two angiogenesis inhibitors have been developed that have a broad spectrum of anticancer activity, yet virtually no side effects. Endogenous angiogenesis inhibitors act as tumor suppressor proteins. The angiogenic response in vivo is based on the genetic background of the host. Several types of angiogenesis inhibitors reveal a biphasic, U-shaped curve of efficacy. "Antiangiogenic chemotherapy" is a novel approach to the treatment of drug resistance.

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Section: Caplostatinmentioning

confidence: 99%

“…TNP-470 also showed significant inhibition of tumors in clinical trials, including durable complete regressions (48,49). The clinical utility of TNP-470, however, was limited by neurotoxicity.…”

Section: Caplostatinmentioning

confidence: 99%

Angiogenesis

2006

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Concise stereocontrolled routes to fumagillol, fumagillin, and TNP‐470

2003

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A concise, diastereoselective synthesis of (+/-)-fumagillol (3) and formal, enantioselective syntheses of the potent angiogenesis inhibitors fumagillin (1) and TNP-470 (2) are reported. The origin of asymmetry is a highly diastereoselective Diels-Alder reaction using a diene with a chiral oxazolidinone auxiliary. The stereochemical course of a key conjugate addition reaction is controlled by the cup-shaped architecture of a cis-fused bicyclic enal. Other key steps include a facile hetero-Claisen rearrangement and a site-selective Sharpless epoxidation.

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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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TNP-470

Cited by 6 publications

References 21 publications

Angiogenesis

Angiogenesis

Concise stereocontrolled routes to fumagillol, fumagillin, and TNP‐470

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

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