Russell Johnson

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Potent imidazopyridine-based inhibitors of fatty acid synthase (FASN) are described. The compounds are shown to have antiviral (HCV replicon) activities that track with their biochemical activities. The most potent analogue (compound 19) also inhibits rat FASN and inhibits de novo palmitate synthesis in vitro (cell-based) as well as in vivo.

Abstract 4446: Discovery of tumor types highly susceptible to FASN inhibition and biomarker candidates for clinical analysis

Inhibition of de novo palmitate synthesis by fatty acid synthase (FASN) is a novel cancer therapeutic approach with strong biological rationale. Tumor cells have an increased dependence on FASN-synthesized palmitate compared to non-tumor cells, which obtain many of their required lipids from the extracellular milieu. FASN expression increases with tumor progression in human tumors and associates with chemoresistance, metastasis, and diminished patient survival in many tumor types. Palmitate and palmitate-derived lipids comprise diverse cellular components and function in processes required for tumor cell proliferation and survival. TVB-2640 and TVB-3166 belong to a series of orally available, reversible, potent, and selective FASN inhibitors discovered and developed by 3-V Biosciences that exhibit anti-tumor activity in diverse preclinical tumor models. FASN inhibition induces tumor cell apoptosis by remodeling tumor cell membranes, blocking signal transduction, and reprogramming gene expression. These effects lead to inhibition of anchorage-independent tumor cell growth under lipid-rich conditions and inhibition of in vivo xenograft tumor growth in mice and rats. Studies to understand the mechanisms of action and biological consequences of FASN inhibition are guiding the discovery of tumors highly dependent on FASN activity and biomarkers for assessment of pharmacodynamic activity and patient selection. Using quantitative genomics and a variety of directed analytical approaches, we identified lipid, mRNA, and protein profiles in tumor cells that change in response to FASN inhibition. Subsets of the changes show correlation with FASN inhibitor sensitivity. Marker candidates, such as gene expression signatures that classify in vitro sensitivity to FASN inhibition, are being investigated for detection in clinical human tumor data sets. Our studies also identified FASN inhibitor-mediated mechanisms of action that function in specific tumor types and biomarkers with potential utility for selecting responsive patients and measuring tumor response. Inhibition of the Wnt/b-catenin pathway and expression of TCF-promoter-regulated genes such as c-Myc are examples. Tumors dependent on Wnt/b-catenin activity or with lower intracellular palmitate stores prior to drug treatment may be susceptible to FASN inhibitor treatment. Pairing MYC expression with additional markers improves the performance of MYC as a marker to select tumor cell lines highly sensitive to FASN inhibition. Biomarker candidates from in vitro studies have been examined in vivo using xenograft tumor studies. These preclinical data support 3-V Biosciences’ ongoing Phase I clinical study of a first-in-class FASN inhibitor TVB-2640, and help guide the next steps in its development. Citation Format: Timothy S. Heuer, Richard Ventura, Kasia Mordec, Julie Lai, Joanna Waszczuk, Glenn Hammonds, Marina Fridlib, Russell Johnson, Lily Hu, Allan Wagman, Marie O9 Farrell, Douglas Buckley, George Kemble. Discovery of tumor types highly susceptible to FASN inhibition and biomarker candidates for clinical analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4446. doi:10.1158/1538-7445.AM2015-4446

Abstract B261: Characterization of FASN-selective small-molecule inhibitors in preclinical tumor models.

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 (< 10 nM) and cell-based (<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.