Discovery and structural modification of inhibitors of methionine aminopeptidases from Escherichia coli and Saccharomyces cerevisiae.
A series of pyridine-2-carboxylic acid derivatives were synthesized according to the leads from the screening, and potent inhibitors have been obtained by structural modification. They have shown submicromolar inhibition of the enzymes (for example, for 9n, IC(50) = 130 nM for EcMetAP1 and IC(50) = 380 nM for ScMetAP1). They represent small-molecule MetAP inhibitors with novel structures different from alkylating fumagillin derivatives and peptidic bestatin-based MetAP inhibitor.
Luo
Qun-Li
QL
Chinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Life Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Li
Jing-Ya
JY
Liu
Zhi-Ying
ZY
Chen
Ling-Ling
LL
Li
Jia
J
Qian
Zhen
Z
Shen
Qiang
Q
Li
Yu
Y
Lushington
Gerald H
GH
Ye
Qi-Zhuang
QZ
Nan
Fa-Jun
FJ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology*; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013844:Thiazoles; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases