Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

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• 作者：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 ; L. Mario Amzel ; Dawei Ma ; Jun O. Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3996-4016
• 全文大小：812K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

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鈥?b>4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1鈥?b>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.