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PDBsum entry 4hxx
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Hydrolase/hydrolase inhibitor
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PDB id
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4hxx
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References listed in PDB file
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Key reference
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Title
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Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.
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Authors
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P.Zhang,
X.Yang,
F.Zhang,
S.B.Gabelli,
R.Wang,
Y.Zhang,
S.Bhat,
X.Chen,
M.Furlani,
L.M.Amzel,
J.O.Liu,
D.Ma.
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Ref.
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Bioorg Med Chem Lett, 2013,
21,
2600-2617.
[DOI no: ]
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PubMed id
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Abstract
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Cellular protein synthesis is initiated with methionine in eukaryotes with few
exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of
N-terminal methionine excision are essential for all organisms. In mammals, type
2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP
(MetAP1) has been shown to play a pivotal role in cell proliferation. Our
previous high-throughput screening of a commercial compound library uncovered a
novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2
(HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To
understand the structure-activity relationship (SAR) and to search for analogues
of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58
analogues were acquired through either commercial source or by in-house
synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were
determined. Through this systematic medicinal chemistry analysis, we have
identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element
for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the
pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side
chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR
campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent
inhibitors of purified HsMetAP1 reported to date. In addition, we also performed
crystallographic analysis of one representative inhibitor (26d) in complex with
N-terminally truncated HsMetAP1.
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