Phosphatidylinositol (PI) is an essential phospholipid. Its related phosphatidylinositol kinases (PIK) play important roles in a number of human diseases.
PI4KIIα is a member of the phosphatidylinositol kinase family. This kinase is not only the precursor of the important regulatory phosphoinositides PI(4,5)P2 and PI(3,4,5)P3, but also is an emerging regulatory molecule in trans-Golgi and endosomal trafficking, as well as phagocytosis.

Recently, some researchers proclaim that PI4KIIα can be a potential target for breast cancer therapy. Most of the identified PIKs inhibitors are ATP-competitive, due to isoform-selective inhibitors reduce toxicity by decreasing off-target effects. So it is necessary to single out a substrate-competitive inhibitor.

Today, we will introduce the first reversibly and specific phosphatidylinositol 4-kinase (PI4KIIα) inhibitor PI-273, it can interact directly with PI4KIIα (IC50 = 0.47 μM).

Firstly, Kinetic analysis identifies that PI-273 is a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI). This is contrasted with most other PI kinase inhibitors that bind to the ATP binding site.

Nextly, in vitro, in MCF-7 cells, PI-273 specifically inhibit PI4P production rather than other lipids, such as LPA, PI3P, PI(4,5)P2 and PI(3,4,5)P3.  PI-273 has an inhibitory effect on different breast cancer cell lines, it inhibits MCF-7, T-47D, SK-BR-3, MDA-MB-468, and BT-474 cells growth with IC50 values of 3.5 μM, 3.1 μM, 2.3 μM, 3.9 μM and 2.1 μM, respectively. Meanwhile, the IC50  values for all the Ras-mutant breast cancer cell lines were higher than 10 μM.
Furthermore, In MCF-7, T-47D, and SK-BR-3 cells, PI-273 (48 hours) induces cell apoptosis and blocks the cell cycle at the G2-M phase with different concentrations.

Lastly, In vivo, In a pharmacokinetic study, male Sprague-Dawley (SD) rats are used.  PI-273 (0.5 mg/kg; 1.5 mg/kg) shows a half-life of 0.411 hours for intravenous administration and 1.321 hours for intragastrical administration, and the absolute bioavailability of this compound is 5.1%.  In an MCF-7 BALB/c nude mice xenografts, PI-273 (intraperitoneal injection; 25 mg/kg/day; 15 days) exhibits a significant decrease in mice tumor volume and weight.

In summary, PI-273 is a lead substrate-competitive inhibitor of PI4KIIα, it can significantly inhibit MCF-7 cell-induced breast tumor growth without toxicity.PI-273 can de an optimized therapeutic agent for cancer in the future due to its significance, safety, and efficacy.


Li J, et al. Cancer Res. 2017 Nov 15;77(22):6253-6266.