PP121

PP121 blocks the PI3K pathway by direct inhibition of PI3K/mTOR in two glioblastoma cell lines, U87 and LN229. PP121 potently inhibits the proliferation of a diverse panel of tumor cell lines containing mutations in the PI3-K pathway components PIK3CA, PTEN, or RAS. PP121 induces a G0G1 arrest in most tumor cells. PP121 directly inhibits Src in cells and reverses its biochemical and morphological effects. PP121 potently inhibits the Ret kinase domain in vitro (IC50<1 nM). PP121 potently blocks VEGF stimulated activation of the PI3-K and MAPK pathways. PP121 inhibits VEGFR2 autophosphorylation at low nanomolar concentrations, confirming that this molecule directly targets VEGFR2 in cells. PP121 inhibits Bcr-Abl induced tyrosine phosphorylation in K562 cells as well as BaF3 cells that express Bcr-Abl.

[1]. Apsel B, et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol, 2008, 4(11), 691-699.

[2]. Peng Y, et al. The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121. Biochem Biophys Res Commun. 2015 Sep 11;465(1):137-44.