Abstract 1891: Pharmacological target validation studies of fatty acid synthase in carcinoma using the potent, selective and orally bioavailable inhibitor IPI-9119

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.1891-1891
• Main Authors: Brophy, Erin, Conley, James, O'Hearn, Patrick, Douglas, Mark, Cheung, Culver, Coco, John, D'Anello, Laura, Wylie, Andrew, Tibbitts, Thomas, Keaney, Gregg, Chan, Lawrence, Bahadoor, Adilah, Snyder, Dan, Nevalainen, Marta, Castro, Alfredo, Palombella, Vito, Loda, Massimo, Peluso, Stephane
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-1891

Fatty acid synthase (FASN) is a key enzyme responsible for fatty acids synthesis de novo in mammals. Overexpression of FASN is common in many cancers including prostate, breast and colon cancer and elevated expression of FASN has been linked with poor prognosis and reduced disease-free survival. Experiments with RNAi and small molecule inhibitors suggest that FASN is a metabolic oncogene with an important role in tumor growth and survival and an appealing target for cancer therapy. However, studies utilizing small molecule FASN inhibitors like orlistat and C75 have been confounded by the lack of potency and selectivity, as well as the poor pharmacological properties of these inhibitors. Herein we report pharmacological target validation studies of FASN using a potent, selective and orally bioavailable FASN inhibitor IPI-9119. Building on previous experience with serine hydrolase inhibitors, a series of novel mechanism-based FASN inhibitors were designed based on a tetrazolone carboxamide scaffold. Like orlistat, these analogs are irreversible inhibitors that specifically target the FASN thioesterase domain. Tetrazolone carboxamide analogs were shown to potently inhibit cellular FASN using an occupancy assay and to completely block de novo palmitate synthesis in HCT-116 colon cancer cells using a 13C-glucose incorporation assay. Lead optimization of the tetrazolone carboxamide series resulted in the identification of IPI-9119 as a tool for in vivo proof-of-concept studies. IPI-9119 is a potent FASN inhibitor in both biochemical (IC50∼1nM) and cellular occupancy assays (IC50∼10nM), and shows more than 400-fold selectivity against several additional serine hydrolases. Importantly, IPI-9119 is orally bioavailable and has pharmacokinetic (PK) properties suitable for in vivo pharmacology studies. IPI-9119 was tested for growth inhibition in cancer cell lines in vitro and tumor xenograft models in vivo. Unexpectedly, in contrast to the knock-down studies and to data reported for orlistat and C75, IPI-9119 failed to elicit anti-proliferative effects in multiple cancer cell lines in vitro. Similarly, PK/PD experiments demonstrated that a single oral dose of IPI-9119 at 200 mg/kg leads to complete and sustained blockade of FASN in HCT-116 tumor xenografts, but IPI-9119 failed to show any anti-tumor activity when dosed as a single agent at 200 mg/kg BID for 10 days. In summary, we identified IPI-9119 as a potent, selective and orally bioavailable FASN inhibitor. Prel