生物活性

• 靶点	PI3Kα IC50:5nM

• 描述There three kinds of catalytic subunits of Class IA PI3Ks, p110α, p110β and p110δ. One of the subunits, P110α, is encoded by PIK3CA in human, which is found to be mutated in many human cancers, for example, colorectal cancers, glioblastomas, gastric cancers, hepatocellular carcinomas, breast cancers. Alpelisib, also called as BYL719, is an orally available p110α inhibitor against with IC50 of 5 nM, less potent to p110β (IC50 = 1.2 μM), p110γ (IC50 = 0.25 μM) and PI3Kδ (IC50 = 0.29 μM, measured by biochemical assay). Alpelisib can block the PI3K/Akt signaling pathway resulting in inhibition of Akt phosphorylation in Rat1-myr-p110x cells^[1]. Alpelisib exhibits potent anti-proliferative and anti-tumor activities in lung squamous cell carcinoma (LSCC) in a PIK3CA-dependent manner^[2]. Now Alpelisib is used in phase I/II trials in patients with breast cancer, lung cancer, pancreatic cancer and squamous cell carcinoma etc.^[3].
• 作用机制Alpelisib can interact with the ATP binding pocket of p110α^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  92.1	500-2000 nM	Growth Inhibition Assay	5 d	inhibits the phosphorylation of AKT (Ser473) up to 1 μM	24563540
  AU565	33 μM	Growth Inhibition Assay	5 d	inhibits 26％ cell growth	23918797
  BON-1	1/10 μM	Function Assay	4 h	inhibits PI3K (AKT Ser308) and mTORC1/2 activities	25026292

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• 动物研究
  剂量	Mice[4] (p.o.): 12.5 mg/kg – 50 mg/kg (daily)
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 3 mg/kg 15 mg/kg 0.6 mg/kg Administration p.o. p.o. p.o. Cmax 0.52 µM (dose normal) 0.19 µM (dose normal) 1.07 µM (dose normal) BAV 1.06 0.58 1.4 CL 8 ml/min/kg 10 ml/min/kg 8 ml/mjin/kg

• 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
  NCT02167854	Breast Cancer	Phase 1	Active, not recruiting	June 2019	United States, New Jersey ... more >> Memorial Sloan Kettering at Basking Ridge Basking Ridge, New Jersey, United States, 07920 Memorial Sloan Kettering Monmouth Middletown, New Jersey, United States, 07748 United States, New York Memorial Sloan Kettering Commack Commack, New York, United States, 11725 Memoral Sloan Kettering Westchester Harrison, New York, United States, 10604 Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 Memorial Sloan Kettering Rockville Centre Rockville Centre, New York, United States, 11570 Collapse <<
  NCT02734615	Advanced or Metastatic ER+ Bre... more >>ast Cancer Collapse <<	Phase 1	Recruiting	October 30, 2020	United States, Maryland ... more >> Novartis Investigative Site Recruiting Baltimore, Maryland, United States, 21287 United States, Massachusetts Massachusetts General Hospital Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02114 Contact: Dejan Juric, MD    617-726-6500    Juric.Dejan@mgh.harvard.edu    Contact: Meghan Miles    617-726-6500    MEMILES@mgh.harvard.edu    Principal Investigator: Dejan Juric, MD          United States, New York Novartis Investigative Site Recruiting New York, New York, United States, 10021 Contact: Alexandra Burleigh    646-422-4394    burleiga@mskcc.org    Principal Investigator: Komal Jhaveri          United States, Texas Novartis Investigative Site Recruiting Houston, Texas, United States, 77030 Contact: Daniela Westerhold       diwesterhold@mdanderson.org    Principal Investigator: Rachel M Layman          Belgium Novartis Investigative Site Recruiting Bruxelles, Belgium, 1200 Canada, Ontario Novartis Investigative Site Recruiting Toronto, Ontario, Canada, M5G 2M9 France Novartis Investigative Site Recruiting Lyon Cedex, France, 69373 Italy Novartis Investigative Site Recruiting Milano, MI, Italy, 20133 Novartis Investigative Site Recruiting Milano, MI, Italy, 20141 Japan Novartis Investigative Site Recruiting Koto-ku, Tokyo, Japan, 135 8550 Singapore Novartis Investigative Site Recruiting Singapore, Singapore, 169610 Spain Novartis Investigative Site Recruiting Barcelona, Catalunya, Spain, 08036 Novartis Investigative Site Recruiting Madrid, Spain, 28007 Collapse <<
  NCT03138070	Head and Neck Squamous Cell Ca... more >>ncer Collapse <<	Not Applicable	Recruiting	May 2020	Canada, Ontario ... more >> London Health Sciences Centre, London Regional Cancer Program Recruiting London, Ontario, Canada, N6A 4L6 Contact: Anthony Nichols    519-685-8500 ext 58804    anthony.nichols@lhsc.on.ca    Contact: Shamim Mortuza    519-685-8500 ext 58618    shamim.mortuza@lhsc.on.ca Collapse <<

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• 参考文献

• [1] Furet P, Guagnano V, et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3741-8.

  [2] Bonelli MA, Cavazzoni A, et al. Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations. Mol Cancer Ther. 2015 Aug;14(8):1916-27.

  [3] Zhao HF, Wang J, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017 Jun 7;16(1):100.

  [4] Gobin B, Huin MB, et al. BYL719, a new α-specific PI3K inhibitor: single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma. Int J Cancer. 2015 Feb 15;136(4):784-96.