4IU6

Human Methionine Aminopeptidase in complex with FZ1: Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1

Summary for 4IU6

• Entry DOI: 10.2210/pdb4iu6/pdb
• Related: 2G6P 4HXX
• Descriptor: Methionine aminopeptidase 1, COBALT (II) ION, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: metap1, methionine aminopeptidase 1, methionine aminopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43805.38

Authors

Gabelli, S.B.,Zhang, F.,Miller, M.,Liu, J.,Amzel, L.M. (deposition date: 2013-01-19, release date: 2013-05-01, Last modification date: 2024-02-28)

Primary citation

Zhang, F.,Bhat, S.,Gabelli, S.B.,Chen, X.,Miller, M.S.,Nacev, B.A.,Cheng, Y.L.,Meyers, D.J.,Tenney, K.,Shim, J.S.,Crews, P.,Amzel, L.M.,Ma, D.,Liu, J.O.
Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells.
J.Med.Chem., 56:3996-4016, 2013

PubMed 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.

PubMed: 23634668
DOI: 10.1021/jm400227z

Experimental method

X-RAY DIFFRACTION (1.9 Å)