生物活性

• 靶点

  p110β IC50:33nM

  p110γ IC50:75nM

  PI3Kα IC50:3nM

  PI3Kδ IC50:3nM

• 描述Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that catalyze the phosphorylation of the 3-hydroxyl position of phosphatidylinositides and participate in several cellular process. Up to now, there are eight PI3 kinases have been identified, which are divided into classes IA, 1B, II, and III based on the sequence homology and substrate preference. GDC-0941 is a potent, selective and orally bioavailable inhibitor of class I PI3Ks (p110α IC50=3nM, p110δ IC50=3nM, p110β IC50=33nM, p110γ IC50=75nM, measured by scintillation proximity assay), with less potency to mTOR (IC50=0.58μM, measured by HTRF assay)^[1]. GDC-0941 is a derivative of PI-103, a dual PI3K/mTOR inhibitor, and has good pharmacokinetic properties. Its oral bioavailability is up to 78% in subcutaneous U-87 MG xenograft mice and shows sustained and remarkable inhibition of Akt phosphorylation and tumor growth, up to 98%^[2]. GDC-0941 barely penetrated through the intact BBB^[3].
• 作用机制GDC-0941 is a potent, ATP competitive inhibitor of p110α with Ki value of 10.2±4.4 nM.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=2.45617 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=2.71035 μM	SANGER
  639-V	-	Growth Inhibition Assay	-	IC50=1.50245 μM	SANGER

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• 动物研究
  剂量	Mice: min = 75 mg/kg[4], max = 150 mg/kg[5] Nude Mice: min = 25 mg/kg bid, max = 50 mg/kg bid[6]
  给药途径	p.o

• 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
  NCT02430363	Glioblastoma	Phase 1 Phase 2	Unknown	June 2018	United States, Massachusetts ... more >> Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, Texas M D Anderson Cancer Center Houston, Texas, United States, 77030 Belgium UCL- Cliniques Universitaires Saint Luc Brussels, Belgium Germany St Johannes Hospital Duisburg, Germany, 47166 Italy Spedali Civili di Brescia Brescia, Italy IRCCS San Raffaele Milan, Italy Poland Lower-Silesian Oncology Centre Wroclaw, Lower-Silesian, Poland, 53413 Russian Federation Pavlov State Medical University St. Petersburg, Russian Federation, 197089 Spain Hospital Universitario Germans Trias I Pujol Barcelona,, Spain Switzerland Universitätsklinik für Frauenheilkunde Bern, Switzerland Ukraine Regional Cancer Center Dnepropetrovsk, Ukraine, 49000 National Institute of Cancer Kiev, Ukraine, 03035 United Kingdom Royal Victoria Hospital Belfast, Ulster, United Kingdom, BT12 6BA Collapse <<
  NCT02389842	Advanced Solid Tumours ... more >> Breast Cancer Collapse <<	Phase 1	Unknown	August 2017	United Kingdom ... more >> The Royal Marsden NHS Foundation Trust Recruiting London, United Kingdom, SM2 5PT Contact: Timothy Yap, PhD    02086613539    timothy.yap@icr.ac.uk    Principal Investigator: Timothy Yap, PhD          The Christie NHS Foundation Trust Not yet recruiting Manchester, United Kingdom, M20 4BX Contact: Anne Amstrong, MBBS    0161 446 3746    elaine.mercer@christie.nhs.uk    Principal Investigator: Anne Armstrong, MBBS Collapse <<
  NCT02092831	Healthy Volunteer	Phase 1	Completed	-	United States, Wisconsin ... more >> Madison, Wisconsin, United States, 53704 Collapse <<

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• 参考文献

• [1] Folkes AJ, Ahmadi K, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d] pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem. 2008 Sep 25;51(18):5522-32.

  [2] Raynaud FI, Eccles SA, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther. 2009 Jul;8(7):1725-38.

  [3] Salphati L, Shahidi-Latham S, et al. Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging. Drug Metab Dispos. 2014 Jul;42(7):1110-6.

  [4] Garcia-Martínez JM, Wullschleger S, et al. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011;104(7):1116-25.

  [5] Wallin JJ, Guan J, et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo. Clin Cancer Res. 2012;18(14):3901-11.

  [6] Burrows N, Babur M, et al. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways. J Clin Endocrinol Metab. 2011;96(12):E1934-43.

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