TASP0415914 is an Orally Active PI3Kγ Inhibitor

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that catalyze the phosphorylation of the 3-hydroxyl position of the inositol ring. A wide variety of different stimuli activate PI3Ks. The stimuli include growth factors, inflammatory mediators, hormones, neurotransmitters, immunoglobulins, and antigens. PI3Ks have relations with the regulation of numerous biological processes, including cell growth, differentiation, survival, proliferation, migration, and metabolism. The expression of PI3Kγ is limited to hematopoietic and endothelial cells. PI3Kγ knockout mice have shown that PI3Kγ is essential for T-cell and B-cell development and functionalities.  PI3Kγ is also essential for neutrophil and mast cell migration as well as mast cell degranulation. It may be a valuable therapeutic target for inflammatory disorders, such as rheumatoid arthritis. TASP0415914 is an orally potent inhibitor of PI3Kγ. TASP0415914 demonstrates good potency in a cell-based assay. Furthermore, it exhibited in vivo efficacy in a collagen-induced arthritis model in mice.

TASP0415914 (compound 8j) shows high metabolic stability in rat/human liver microsomes. In addition, TASP0415914 has no CYP inhibition up to 10 μM for CYP1A2, 2C9, 2C19, 2D6, and 3A4. It also suppresses the progression of the disease in a dose-dependent manner in a mouse collagen-induced arthritis (CIA) model. In detail, it suppresses the progression of the disease compared with vehicle control, at 30 and 100 mg/kg in a dose-dependent manner.

In summary, TASP0415914 exhibits good potency in a cell-based assay and in vivo efficacy using a therapeutic CIA mouse model after oral administration. TASP0415914 is a promising lead as an orally potent PI3Kγ inhibitor. It has the potential for the research of inflammatory diseases.


Yusuke Oka, et al. Bioorg Med Chem. 2013 Dec 15;21(24):7578-83.