PI-273 是一种可逆的特异性磷脂酰肌醇 4-激酶抑制剂，IC50为 0.47 μM。它可抑制乳腺癌细胞的增殖，阻断细胞周期并诱导细胞凋亡。

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

PI-273 exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC50 = 0.47 μmol/L) and suppressed cell proliferation.?Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα.?The kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site.?PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα.?Mutant analysis revealed the role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα.?In addition, PI-273 treatment retarded cell proliferation by blocking cells in G2-M, inducing cell apoptosis and suppressing colony-forming ability.?Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity.?PI-273 is the first substrate-competitive, a subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target.

PI-273 (intraperitoneal injection; 25 mg/kg/day; 15 days) profoundly suppresses the tumor volume and weight in the MCF-7 xenografts[1].PI-273 (0.5 mg/kg (intravenously) or 1.5 mg/kg (intragastrically); 0.08-5 hours) has a half-life of 0.411 hours for intravenous administration and 1.321 hours for intragastrical administration, and the absolute bioavailability of PI-273 is 5.1%[1].

925069-34-7

C16H16ClN3O2S2

381.9

DMSO:6 mg/mL (15.71 mM),ultrasonic and warming and heat to 60°C
Powder: -20°C for 3 years
In solvent: -80°C for 2 years