Pyridinylquinazolines
Selectively Inhibit Human Methionine
Aminopeptidase‑1 in Cells
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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