Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase‑1 in Cells

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 (<i>Hs</i>MetAP1)-selective inhibitors (<b>1</b>–<b>4</b>), but all of them failed to inhibit cellular <i>Hs</i>MetAP1. Using Mn­(II) or Zn­(II) to activate <i>Hs</i>MetAP1, we found that <b>1</b>–<b>4</b> could only effectively inhibit purified <i>Hs</i>MetAP1 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 <i>Hs</i>MetAP1 without Co­(II). Subsequently, we demonstrated that <b>11j</b>, an auxiliary metal-dependent inhibitor, effectively inhibited <i>Hs</i>MetAP1 in primary cells. This is the first report that an <i>Hs</i>MetAP1-selective inhibitor is effective against its target in cells