Voxtalisib

Voxtalisib is a dual inhibitor of PI3K and mammalian target of rapamycin complex (mTORC; IC₅₀s = 39, 110, 43, 9, 160, and 910 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, mTORC1, and mTORC2, respectively).¹ It is selective for these kinases over vacuolar protein sorting 34 (VPS34; IC₅₀ = 9,100 nM) and a panel of 130 additional protein kinases at 1.5 ?M but does inhibit DNA protein kinase (DNA-PK; IC₅₀ = 150 nM). Voxtalisib decreases EGF-induced production of PIP₃, a product of PI3K-mediated PIP₂ metabolism, in PC3 prostate cancer cells with an IC₅₀ value of 290 nM. It also reduces phosphorylation of the PI3K and mTORC targets Akt and ribosomal protein S6 (S6RP) in the same model (IC₅₀s = 250 and 120 nM, respectively). Voxtalisib inhibits proliferation and colony formation of PC3 cells (IC₅₀s = 1,800 and 270 nM, respectively). It reduces tumor growth and increases survival in a GBM-39 glioblastoma multiforme (GBM) mouse xenograft model when administered at a dose of 30 mg/kg twice per day alone or in combination with temozolomide .²

1.Yu, P., Laird, A.D., Du, X., et al.Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathwayMol. Cancer Ther.13(5)1078-1091(2014) 2.Prasad, G., Sottero, T., Yang, X., et al.Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomideNeuro. Oncol.13(4)384-392(2011)