Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells

Feiran Zhang, Shridhar Bhat, Sandra Gabelli, Xiaochun Chen, Michelle Susan Miller, Benjamin A Nacev, Yim Ling Cheng, David J Meyers, Karen Tenney, Joong Sup Shim, Phillip Crews, L Mario Amzel, Dawei Ma, Jun Liu

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3996 - 4016
Number of pages21
JournalJournal of Medicinal Chemistry
Volume56
Issue number10
DOIs
Publication statusPublished - 2013

Cite this

Zhang, F., Bhat, S., Gabelli, S., 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. (2013). Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells. Journal of Medicinal Chemistry, 56(10), 3996 - 4016. https://doi.org/10.1021/jm400227z