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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2

Jieyi Wang1, George S Sheppard, Pingping Lou

  • 1Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, IL 60064, USA. Jieyi.Wang@abbott.com

Cancer Research
|November 25, 2003
PubMed

Insights

A new reversible inhibitor of methionine aminopeptidase (MetAP)-2, A-357300, effectively suppresses tumor growth and angiogenesis. This novel cancer therapeutic agent shows promise without the toxicities associated with previous irreversible inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Methionine aminopeptidase (MetAP)-2 is a potential cancer therapy target, with TNP-470 being an irreversible inhibitor.
  • The precise role of MetAP2 in tumor progression was unclear due to limitations of irreversible inhibitors.

Purpose of the Study:

  • To investigate the efficacy and safety of a novel, rationally designed reversible MetAP2 inhibitor, A-357300.
  • To determine the therapeutic potential of reversible MetAP2 inhibition in preclinical cancer models.

Main Methods:

  • Synthesis of a bestatin-type reversible MetAP2 inhibitor (A-357300) using crystal structure data and parallel synthesis.
  • Evaluation of A-357300's effects on cell cycle, angiogenesis in vitro and in vivo, and antitumor efficacy in various murine cancer models.

Main Results:

  • A-357300 selectively induces G(1) cell cycle arrest in endothelial and some tumor cells, but not most primary non-endothelial cells.
  • The inhibitor demonstrated significant inhibition of angiogenesis both in vitro and in vivo.
  • A-357300 exhibited potent antitumor efficacy across carcinoma, sarcoma, and neuroblastoma models.

Conclusions:

  • Methionine aminopeptidase (MetAP)-2 plays a critical role in cell growth and tumor progression.
  • Reversible MetAP2 inhibitors, exemplified by A-357300, represent a promising new class of cancer therapeutics with a potentially improved safety profile.

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