Voxtalisib (XL765) (C09-1082-651)

InformationVoxtalisib (SAR245409, XL765) is a dual inhibitor ofmTOR/PI3K, mostly forp110γwithIC50of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.TargetsPI3Kγ (Cell-free assay); PI3Kα (Cell-free assay); PI3Kδ (Cell-free assay); PI3Kβ (Cell-free assay); DNA-PK (Cell-free assay) 15964,9 nM; 39 nM; 43 nM; 113 nM; 150 nMIn vitroXL765 is active against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110α, β, γ and δ, respectively). XL765 also inhibits DNA-PK (IC50 = 150 nM) and mTOR (IC50 = 157 nM) but not XL-147 which shows IC50 values of > 15 μM. XL765 treatment results in decreased cell viability in 13 PDA cell lines in a dose-dependent manner. XL765, a dual-target PI3K/mTOR inhibitor, inhibits cell growth and apoptosis in many more cell lines and at lower concentrations as compared to the PI3K-selective inhibitors XL147 and PIK90. The effect can be recapitulated by using combinations of single-targeted compounds. XL765 significantly reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which is associated with greater apoptosis induction rather than to PI3K inhibition alone. XL765 treatment causes accumulation of autophagosomes in MIAPaCa-2 cells, and results in significant dose-dependent AVO induction and LC3-II stimulation in MIAPaCa-2 cells stably expressing a LC3-GFP construct.In vivoThe combination of XL765 (30 mg/kg) with chloroquine (50 mg/kg) results in significant inhibition of BxPC-3 xenograft growth in mice models, while XL765 alone at the same dose has no inhibitory effect. Oral administration of XL765 results in greater than 12-fold reduction in median tumor bioluminescence compared to control and improvement in median survival in nude mice implanted intracranially with GBM 39-luc cells. XL765 in combination with temozolomide (TMZ) yields a 140-fold reduction in median bioluminescence with a trend toward improvement in median survival compared with TMZ alone.Cell Research(from reference)Cell lines：Pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc10.05, Panc8.13, BxPC-3, etc.) Concentrations：Dissolved in DMSO, final concentration ~10 μM Incubation Time：24, 48, 72 hours. Specifications and Purity: 99%. Molecular Formula: C13H14N6O. Molecular Weight: 270.29. PubChem CID: 16123056. Isomeric SMILES: CCN1C2=NC(=NC(=C2C=C(C1=O)C3=CC=NN3)C)N.