Recent advances of desymmetrization protocol applied in natural product total synthesis

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Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity.

Steven Kridel, Fumiko Axelrod, Natasha Rozenkrantz … (2004)

One of the fundamental principles of pharmacology is that most drugs have side effects. Although considerable attention is paid to detrimental side effects, drugs can also have beneficial side effects. Given the time and expense of drug development, it would be particularly exciting if a systematic method could be applied to reveal all of the activities, including the unappreciated actions, of a potential drug. The present study takes the first step along this path. An activity-based proteomics strategy was used to simultaneously identify targets and screen for their inhibitors in prostate cancer. Orlistat, a Food and Drug Administration-approved drug used for treating obesity, was included in this screen. Surprisingly, we find a new molecular target and a potential new application for Orlistat. Orlistat is a novel inhibitor of the thioesterase domain of fatty acid synthase, an enzyme strongly linked to tumor progression. By virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3 tumors in nude mice.

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Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells.

Joy L Little, Frances Wheeler, Diane Fels … (2007)

Fatty acid synthase (FAS), the cellular enzyme that synthesizes palmitate, is expressed at high levels in tumor cells and is vital for their survival. Through the synthesis of palmitate, FAS primarily drives the synthesis of phospholipids in tumor cells. In this study, we tested the hypothesis that the FAS inhibitors induce endoplasmic reticulum (ER) stress in tumor cells. Treatment of tumor cells with FAS inhibitors induces robust PERK-dependent phosphorylation of the translation initiation factor eIF2alpha and concomitant inhibition of protein synthesis. PERK-deficient transformed mouse embryonic fibroblasts and HT-29 colon carcinoma cells that express a dominant negative PERK (DeltaC-PERK) are hypersensitive to FAS inhibitor-induced cell death. Pharmacologic inhibition of FAS also induces the processing of X-box binding protein-1, indicating that the IRE1 arm of the ER stress response is activated when FAS is inhibited. Induction of ER stress is further confirmed by the increased expression of the ER stress-regulated genes CHOP, ATF4, and GRP78. FAS inhibitor-induced ER stress is activated prior to the detection of caspase 3 and PARP cleavage, primary indicators of cell death, whereas orlistat-induced cell death is rescued by coincubation with the global translation inhibitor cycloheximide. Lastly, FAS inhibitors cooperate with the ER stress inducer thapsigargin to enhance tumor cell killing. These results provide the first evidence that FAS inhibitors induce ER stress and establish an important mechanistic link between FAS activity and ER function.