IPI-9119 is an Orally Active, Selective and Irreversible FASN Inhibitor
Posted On 2020-09-02
Fatty acid synthase (FASN) is a multi-enzyme protein that catalyzes the synthesis of fatty acids. Its main function is to catalyze the synthesis of palmitate (C16:0) from acetyl CoA and malonyl COA in the presence of NADPH. Specifically, FASN is a key enzyme responsible for the synthesis of fatty acids from scratch. Besides, overexpression of FASN is common in many cancers, including prostate cancer, breast cancer, and colon cancer. Moreover, inhibition of FASN activity by genetic and pharmacological methods can inhibit the growth of PCa cells through cell cycle arrest and/or apoptosis. Furthermore, FASN is a metabolic oncogene, which plays an important role in tumor growth and survival, and is an effective target for cancer treatment. IPI-9119 is an orally active, selective, and irreversible FASN inhibitor.
IPI-9119 is an orally active, selective, and irreversible FASN inhibitor with anti-cancer activity.
But, how does IPI-9119 protect against cancer cells via FASN? Let’s discuss it in detail. First of all, IPI-9119 is an orally active, selective, and irreversible FASN inhibitor with an IC50 of 0.3 nM in vitro biochemical assay. Meanwhile, IPI-9119 inhibits tumor growth of castration-resistant prostate cancer (CRPC) xenografts mouse models.
In the second place, IPI-9119 inhibits FASN in cellular occupancy assays (IC50∼10nM). And it shows more than 400-fold selectivity against several additional serine hydrolases. Nonetheless, IPI-9119 (0.1-0.5 μM) inhibits cell growth and induces cell cycle arrest, apoptosis. Interestingly, IPI-9119 has no growth inhibition in FASN KO PCa cells. IPI-9119 reduced the proportion of S-phase cells and increased that of G0/G1-, sub-G1–phase cells, and decreased expression of cyclin A2. Importantly, IPI-9119 significantly decreased AR-FL protein levels in AD LNCaP, AI C4-2 cells (expressing only AR-FL). Particularly, IPI-9119 reduced the expression of AR-V7 in LNCaP-95, 22Rv1 AI cells driven by this variant.
Last but not the least, IPI-9119 (SC pump infusion) inhibits tumor growth of castration-resistant prostate cancer (CRPC) xenografts mouse models with 100 mg/mL for 28 days.
All in all, IPI-9119 is an orally active, selective, and irreversible FASN inhibitor with anti-cancer activity.
Giorgia Zadra, et al. Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):631-640.