Abstract B261: Characterization of FASN-selective small-molecule inhibitors in preclinical tumor models.
Authors: Heuer Timothy S. , Chen Minchao , Ventura Richard , Waszczuk Joanna , Yendluri Satya , Lai Julie , Tep Samnang , Feng Shirley , Johnson Russell , Zaharia Cristiana , Buckley Douglas , Kemble George 
Published: August 2014

Abstract
The purpose of this study is to characterize the activity of small-molecule FASN inhibitors in preclinical models of human cancer to evaluate their potential utility as novel cancer therapeutics. FASN-synthesized palmitate is required for vital cellular processes that include energy metabolism, cellular membrane biosynthesis, and protein localization and function. Many solid and hematopoietic tumors overexpress FASN. Moreover, tumor expression of FASN is increased in a stage-dependent manner that is correlated with patient survival. FASN activity can promote the tumorigenic capacity of cells by multiple mechanisms that include: activating cell growth and survival signal transduction pathways such as PI3K-AKT and enhancing cellular processes such as macromolecular biosynthesis, cellular stress response, and energy metabolism. 3-V Biosciences has discovered and developed a series of selective, reversible FASN inhibitors that have been optimized and characterized using in vitro and in vivo assays. These molecules are highly active in both in vitro and in vivo studies, and selected FASN inhibitors demonstrate excellent biochemical (&lt; 10 nM) and cell-based (&lt;100 nM) IC50 values. In vitro, inhibitory activity of cell-based palmitate synthesis aligns with activity in cell phenotypic (e.g. growth and viability) and mechanistic (e.g. AKT phosphorylation and PARP cleavage) assays in cell lines derived from pancreas, breast, lung, colon, and other tumor tissues. Moreover, pharmacologic supplementation of palmitate to cell culture medium rescues cells from cell death in FASN-inhibition cell viability assays. Together, these data show that in vitro FASN inhibition is associated with growth-inhibitory and apoptosis-inducing effects. These novel FASN inhibitors show oral bioavailability, dose dependent plasma exposure, and demonstrate excellent in vivo pharmacodynamic activity. Tumor xenograft studies in mice have been conducted with the FASN inhibitor TVB-3166, and the results demonstrate in vivo tumor growth inhibition both as a single agent and in combination with standard of care chemotherapy agents. TVB-3166 in combination with different chemotherapy agents shows synergistic or additive anti-tumor efficacy in these xenograft studies. In conclusion, these data support continued investigation of FASN inhibition as an approach for the development of a novel cancer therapeutic with the potential for anti-tumor activity in multiple tumor types. Further characterization of FASN inhibitor activity as a single agent and in combination with chemotherapeutics is ongoing using cell-based mechanistic and phenotypic assays as well as tumor xenograft studies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B261.
Citation Format: Timothy S. Heuer, Minchao Chen, Richard Ventura, Joanna Waszczuk, Satya Yendluri, Julie Lai, Samnang Tep, Shirley Feng, Russell Johnson, Cristiana Zaharia, Douglas Buckley, George Kemble. Characterization of FASN-selective small-molecule inhibitors in preclinical tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B261.