title: Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells.
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.
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Feiran
authors: F
authors: Zhang
authors: Shridhar
authors: S
authors: Bhat
authors: Sandra B
authors: SB
authors: Gabelli
authors: Xiaochun
authors: X
authors: Chen
authors: Michelle S
authors: MS
authors: Miller
authors: Benjamin A
authors: BA
authors: Nacev
authors: Yim Ling
authors: YL
authors: Cheng
authors: David J
authors: DJ
authors: Meyers
authors: Karen
authors: K
authors: Tenney
authors: Joong Sup
authors: JS
authors: Shim
authors: Phillip
authors: P
authors: Crews
authors: L Mario
authors: LM
authors: Amzel
authors: Dawei
authors: D
authors: Ma
authors: Jun O
authors: JO
authors: Liu
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D003035:Cobalt / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D008345:Manganese / Q000494:pharmacology; D008670:Metals / Q000737:chemistry; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D015032:Zinc / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D007202:Indicators and Reagents; D008670:Metals; D011480:Protease Inhibitors; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D003035:Cobalt; D008345:Manganese; D008715:Methionine; D000626:Aminopeptidases; C511921:METAP1D protein, human; D015032:Zinc; D013936:Thymidine
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