Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells

Feiran Zhang, Shridhar Bhat, Sandra B Gabelli, Xiaochun Chen, Michelle S. Miller, Benjamin A. Nacev, Yim Ling Cheng, David J Meyers, Karen Tenney, Joong Sup Shim, Phillip Crews, Mario L Amzel, Dawei Ma, Jun Liu

Research output: Contribution to journalArticle

Abstract

Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.

Original languageEnglish (US)
Pages (from-to)3996-4016
Number of pages21
JournalJournal of Medicinal Chemistry
Volume56
Issue number10
DOIs
Publication statusPublished - May 23 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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