Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity.
Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 muM IC(50) and having no effect on human ACC1 at 100 muM.
Marjanovic
Jasmina
J
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
Chalupska
Dominika
D
Patenode
Caroline
C
Coster
Adam
A
Arnold
Evan
E
Ye
Alice
A
Anesi
George
G
Lu
Ying
Y
Okun
Ilya
I
Tkachenko
Sergey
S
Haselkorn
Robert
R
Gornicki
Piotr
P
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D040461:Gene Components; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy*; D030781:Organisms, Genetically Modified; D015003:Yeasts
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase