1431939-93-3Relevant articles and documents
Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells
Zhang, Feiran,Bhat, Shridhar,Gabelli, Sandra B.,Chen, Xiaochun,Miller, Michelle S.,Nacev, Benjamin A.,Cheng, Yim Ling,Meyers, David J.,Tenney, Karen,Shim, Joong Sup,Crews, Phillip,Amzel, L. Mario,Ma, Dawei,Liu, Jun O.
, p. 3996 - 4016 (2013/07/19)
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.
