A dual inhibitor of PI3K and mTORC
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)
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