Voxtalisib (XL765) (SAR245409, XL765) is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.

p110γ:9 nM

Voxtalisib对第一类PI3K具有活性（IC50分别为p110α、β、γ和δ的39、113、9和43 nM）。Voxtalisib还抑制DNA-PK（IC50 = 150 nM）和mTOR（IC50 = 157 nM），但不抑制XL-147，后者的IC50值> 15 μM。[1] Voxtalisib处理以剂量依赖性方式降低了13种PDA细胞系的细胞活力。作为双重靶点PI3K/mTOR抑制剂的Voxtalisib，与PI3K选择性抑制剂XL147和PIK90相比，在更多的细胞系中抑制细胞生长和诱导凋亡，并且所需浓度更低。这种效应可以通过使用单一靶向化合物的组合来重现。Voxtalisib显著降低mTOR靶标S6、S6K和4EBP1的磷酸化水平，这与通过诱导更多的凋亡而非仅仅PI3K抑制相关。Voxtalisib处理导致MIAPaCa-2细胞中自噬体的积累，并在稳定表达LC3-GFP构建的MIAPaCa-2细胞中引起显著的剂量依赖性AVO诱导和LC3-II激活。[2]

Voxtalisib（30 mg/kg）与氯喹（50 mg/kg）结合在小鼠的BxPC-3异种移植瘤生长模型中显著抑制瘤体生长，而单独使用相同剂量的Voxtalisib并无抑制效果。[2] 经口给予Voxtalisib能使GBM 39-luc细胞内植入裸鼠的肿瘤生物发光中值降低超过12倍，与对照组相比，显著提高了裸鼠的中位生存期。Voxtalisib与替莫唑胺（TMZ）联合使用，可使肿瘤生物发光中值降低140倍，并且与单独使用TMZ相比，呈现出中位生存期改善的趋势。[3]

Cells are treated with XL765 24 hours after plating and harvested for apoptosis or autophagy assays at 24, 48, or 72 hours after XL765 treatment. Apoptosis is determined by total percentage of annexin V-positive cells by fluorescence-activated cell sorting (FACS). Acidic vesicular organelles (AVOs) are detected in XL765-treated cells by vital staining with acridine orange. The degree of AVO formation is expressed as fold increase of acridine orange fluorescence intensity (FL3) in XL765-treated cells versus control cells. (Only for Reference)