Fatty Acid Synthase Inhibitor II, GSK2194069

A cell-permeable, aqueous soluble (79 µg/mL or 184 µM) triazolone compound that selectively inhibits the β-ketoacyl reductase (KR) activity of fatty acid synthase (FAS) in a reversible (IC₅₀ in nM/h of pre-incubation = 13/0, 16/1, 15/4.7, 14/7; 2 nM hFAS/4 mM trans-1-decalone/ 48 nM drug), trans-1-decalone-competitive (K_i = 10 nM), and NADPH-uncompetitive manner by targeting FAS in its NADPH-bound, but not free or NADP⁺-bound form, while exhibiting little or no potency toward FAS β-ketoacyl synthase (KS), β-hydroxyoacyl dehydratase (DH), enoyl reductase (ER), or thioesterase (TE) domain activity. Shown to effectively inhibit de novo FA synthesis in cancer cultures (by >70% in KATO-III, MKN45, SNU-1, and A549 cells;100 nM for 24 h) with a concomitant accumulation of cellular FAS substrate malonyl-CoA (13-fold of control using A549 cells; 30 nM for 48 h) and a drop in phosphatidylcholine level (IC₅₀ = 15.5 nM in 48 h-treated A549 cultures), resulting in an effective growth inhibition in A549 cultures (GI₅₀/5 d = 15 nM) reversible with palmitate co-treatment.

A cell-permeable, aqueous soluble (79 µg/mL or 184 µM) triazolone compound that selectively inhibits the β-ketoacyl reductase (KR) activity of fatty acid synthase (FAS) in a reversible (IC₅₀ in nM/h of pre-incubation = 13/0, 16/1, 15/4.7, 14/7; 2 nM hFAS/4 mM trans-1-decalone/ 48 nM drug), trans-1-decalone-competitive (K_i = 10 nM), and NADPH-uncompetitive manner by targeting FAS in its NADPH-bound, but not free or NADP⁺-bound form, while exhibiting little or no potency toward FAS β-ketoacyl synthase (KS), β-hydroxyoacyl dehydratase (DH), enoyl reductase (ER), or thioesterase (TE) domain activity. Shown to effectively inhibit de novo FA synthesis in cancer cultures (by >70% in KATO-III, MKN45, SNU-1, and A549 cells;100 nM for 24 h) with a concomitant accumulation of cellular FAS substrate malonyl-CoA (13-fold of control using A549 cells; 30 nM for 48 h) and a drop in phosphatidylcholine level (IC₅₀ = 15.5 nM in 48 h-treated A549 cultures), resulting in an effective growth inhibition in A549 cultures (GI₅₀/5 d = 15 nM) reversible with palmitate co-treatment.

Please note that the molecular weight for this compound is batch-specific due to variable water content.

GSK2194069; 1332331-08-4; FASN Inhibitor; FAS Inhibitor

Cell permeable: yes

Primary Target
β-ketoacyl reductase (KR) activity of fatty acid synthase

Toxicity: Standard Handling (A)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Hardwicke, M.A., et al. 2014. Nat. Chem. Biol.10, 774.

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