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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Alwarawrah, Y; Hughes, P; Loiselle, D; Carlson, DA; Darr, DB; Jordan, JL; Xiong, J; Hunter, LM; Dubois, LG; Thompson, JW; Kulkarni, MM; Ratcliff, AN; Kwiek, JJ; Haystead, TAJ

Published Date

  • June 23, 2016

Published In

Volume / Issue

  • 23 / 6

Start / End Page

  • 678 - 688

PubMed ID

  • 27265747

Pubmed Central ID

  • PMC6443244

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2016.04.011


  • eng

Conference Location

  • United States