Evidence map›Paper›PMID 24900682›Full record

ArticleACS medicinal chemistry letters2013

Orally active fumagillin analogues: transformations of a reactive warhead in the gastric environment.

Christopher C Arico-Muendel, Heather Blanchette, Dennis R Benjamin, Teresa M Caiazzo, Paolo A Centrella, Jennifer DeLorey, Elisabeth G Doyle, Steven R Johnson, Matthew T Labenski, Barry A Morgan and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ACS medicinal chemistry letters, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Christopher C Arico-MuendelPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Heather BlanchettePraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Dennis R BenjaminPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Teresa M CaiazzoPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Paolo A CentrellaPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Jennifer DeLoreyPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Elisabeth G DoylePraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Steven R JohnsonPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Matthew T LabenskiPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Barry A MorganPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Gary O'DonovanPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Amy A SarjeantPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Steven SkinnerPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Charles D ThompsonPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Sarah T GriffinPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
William WestlinPraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Kerry F WhitePraecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition.

Indexed as

angiogenesis inhibitorFumagillinirreversible inhibitorMetAP2PPI-2458

Identifiers

PMID24900682
PMCPMC4027436

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.