Novel antagonists of the thioesterase domain of human fatty acid synthase.
Fatty acid synthase (FAS) is up-regulated in a wide range of cancers and has been recently identified as a potential therapeutic target. Indeed, previous research has shown that inhibition of FAS with active site-modifying agents can block tumor cell proliferation, elicit tumor cell death, and prevent tumor growth in animal models. Here, we use a high-throughput fluorogenic screen and identify a novel pharmacophore, 5-(furan-2-ylmethylene) pyrimidine-2,4,6-trione, which inhibits the thioesterase domain of FAS. The novel antagonists are competitive inhibitors of the thioesterase domain, inhibit de novo fatty acid synthesis, and elicit FAS-dependent tumor cell death. This set of novel FAS antagonists provides an important pharmacologic lead for further development of anticancer therapeutics.
Richardson
Robyn D
RD
Cancer Research Center and Center on Proteolytic Pathways, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Smith
Jeffrey W
JW
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020035:Holoenzymes / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D020035:Holoenzymes; D064429:Fatty Acid Synthases