Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase

Valerie E. Fako, Xi Wu, Beth Pflug, Jing Yuan Liu, Jian Ting Zhang

Research output: Contribution to journalArticle

22 Scopus citations


Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells.

Original languageEnglish (US)
Pages (from-to)778-784
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number2
StatePublished - Jan 22 2015


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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