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Cell Chem Biol. 2016 Jun 23;23(6):678-88. doi: 10.1016/j.chembiol.2016.04.011. Epub 2016 Jun 2.

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
2
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Departments of Microbial Infection and Immunity and Microbiology, Ohio State University, Room 788, BRT460 West 12th Avenue, Columbus, OH 43210, USA.
4
Departments of Microbial Infection and Immunity and Microbiology, Ohio State University, Room 788, BRT460 West 12th Avenue, Columbus, OH 43210, USA. Electronic address: jesse.kwiek@osumc.edu.
5
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: timothy.haystead@dm.duke.edu.

Abstract

Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.

PMID:
27265747
DOI:
10.1016/j.chembiol.2016.04.011
[Indexed for MEDLINE]
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