生物活性

• 靶点

  PI3Kβ IC50:110nM

  mTOR IC50:160-910nM

  PI3Kα IC50:39nM

  PI3Kδ IC50:43nM

  PI3Kγ IC50:9nM

• 描述Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Voxtalisib (XL765) is a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. XL765 displayed potent inhibitory activity against class I PI3K isoforms p110α, p110β, p110δ, and p120γ, with IC₅₀ values of 39, 110, 43, and 9 nM, respectively, IC₅₀ values of 160 and 910 nM for mTORC1 and mTORC2, respectively. In a vitro study, XL765 inhibits colony growth with an IC₅₀ value of 270 nM in PC-3 cells and 230 nM in MCF7 cells. Oral administration of XL765 (10, 30, 100, or 300 mg/kg) caused a dose-dependent decrease of phosphorylation of AKT, p70S6K, and S6 in the tumors on melanoma xenograft mice, reaching a maximum of 84% inhibition of S6 phosphorylation at 30 mg/kg at 4h^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01390818	Locally Advanced Solid Tumor ... more >> Metastatic Solid Tumor Breast Cancer Non Small Cell Lung Cancer Melanoma Colorectal Cancer Collapse <<	Phase 1	Completed	-	United States, Arizona ... more >> Pinnacle Oncology Hematology Scottsdale, Arizona, United States, 85258 United States, California Cedars Sinai Medical Center Los Angeles, California, United States, 90048 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Tennessee Sarah Cannon Research Institute Nashville, Tennessee, United States, 37205 United States, Texas Cancer Therapy and Research Center San Antonio, Texas, United States, 78229 Italy Merck Serono Research Site Milan, Italy Spain Merck Serono Research Site Madrid, Spain Collapse <<
  NCT01936363	Ovarian Cancer	Phase 2	Completed	-	-
  NCT01596270	Neoplasm Malignant	Phase 1	Completed	-	United States, Michigan ... more >> Investigational Site Number 840001 Detroit, Michigan, United States, 48201 United States, New Jersey Investigational Site Number 840002 New Brunswick, New Jersey, United States, 08903 United States, Texas Investigational Site Number 840003 Dallas, Texas, United States, 75230 Collapse <<

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• 参考文献

• [1] Mirzoeva OK, Hann B, et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J Mol Med (Berl). 2011 Sep;89(9):877-89.

  [2] Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008 Sep 18;27(41):5511-26.

  [3] Yu P, Laird AD, Du X, Wu J, Won KA, Yamaguchi K, Hsu PP, Qian F, Jaeger CT, Zhang W, Buhr CA, Shen P, Abulafia W, Chen J, Young J, Plonowski A, Yakes FM, Chu F, Lee M, Bentzien F, Lam ST, Dale S, Matthews DJ, Lamb P, Foster P. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Ther. 2014 May;13(5):1078-91. doi: 10.1158/1535-7163.MCT-13-0709. Epub 2014 Mar 14. PMID: 24634413.