生物活性

• 靶点

  PI3Kα IC50:35nM

  PI3Kβ IC50:4nM

  PI3Kγ IC50:675nM

  PI3Kδ IC50:12nM

• 描述Several studies have highlighted the dependency of PTEN deficiency to PI3Kβ activity. For example, conditional knockout of PIK3CB, the gene coding for the p110β subunit, can block the formation of prostate tumours in mouse models, which shows the important role of PI3Kβ in the occurrence of prostate tumour driven by PTEN loss/mutant^[1]. AZD8186 is a potent and selective inhibitor of PI3Kβ/δ with IC50 of 4 nM and 12 nM (measured by using a Kinase-Glo Plus Assay Kit), respectively, less potent to PI3Kα (IC50=35 nM)^[2]. Treatment of 3 nM of AZD8186 can inhibit 50% level of PI3Kβ-dependent activation of pAKT-Ser473 in PTEN-null, MDA-MB-468, cell line, as well as 17 nM of AZD8186 can inhibit IgM-stimulated pAKT-Ser473, which is activated through PI3Kδ, in JEKO cells. These indicate AZD8186 selectively inhibits PI3Kβ- andδ-mediated signaling through AKT in vitro. In the study of growth inhibition by AZD8186, it was found that AZD8186 is effective in breast and prostate lines, but show more reliable on loss of PTEN in prostate lines. AZD8186 is effective to combination therapy in prostate cancer preclinical models. 10 and 30 mg/kg AZD8186 with 15 mg/kg docetaxel showed regressions in PC3 tumor model^[3].

• 动物研究
  剂量	Mice: 25 mg/kg, 50 mg/kg[3] (s.c.), 60 mg/kg[2] (p.o.)
  给药途径	s.c., p.o.
  动物药代数据	Animal Mice Dogs Dose 30 μmol/kg Administration p.o. p.o. CL 77 mL/min/kg 36 mL/min/kg F 0.18 0.23 AUC 1.2 μM·h Vd 1.3 L/kg 2.2 L/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
  NCT01884285	Advanced Castrate-resistant Pr... more >>ostate Cancer CRPC Squamous Non-Small Cell Lung Cancer sqNSCLC Triple Negative Breast Cancer TNBC Collapse <<	Phase 1	Recruiting	September 30, 2019	United States, Massachusetts ... more >> Research Site Recruiting Boston, Massachusetts, United States, 02215 United States, Michigan Research Site Recruiting Detroit, Michigan, United States, 48201 United States, New York Research Site Recruiting New York, New York, United States, 10065 United States, Washington Research Site Recruiting Seattle, Washington, United States, 98109 United States, Wisconsin Research Site Recruiting Madison, Wisconsin, United States, 53792-5666 Canada, Ontario Research Site Recruiting Toronto, Ontario, Canada, M5G 2M9 Spain Research Site Recruiting Barcelona, Spain, 08035 Research Site Recruiting Barcelona, Spain, 8036 Research Site Recruiting Pozuelo de Alarcon, Spain, 28223 United Kingdom Research Site Recruiting Cambridge, United Kingdom, CB2 0QQ Research Site Recruiting London, United Kingdom, WC1E 6BT Research Site Recruiting Manchester, United Kingdom, M20 4BX Research Site Recruiting Sutton, United Kingdom, SM1 2DL Collapse <<
  NCT03218826	Advanced Malignant Solid Neopl... more >>asm Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Anatomic Stage IV Breast Cancer AJCC v8 Castration-Resistant Prostate Carcinoma HER2/Neu Negative Metastatic Malignant Solid Neoplasm Metastatic Prostate Carcinoma PIK3CB Gene Mutation Progesterone Receptor Negative Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8 Prognostic Stage IV Breast Cancer AJCC v8 PTEN Gene Mutation PTEN Loss Stage III Prostate Cancer AJCC v8 Stage IIIA Prostate Cancer AJCC v8 Stage IIIB Prostate Cancer AJCC v8 Stage IIIC Prostate Cancer AJCC v8 Stage IV Prostate Cancer AJCC v8 Stage IVA Prostate Cancer AJCC v8 Stage IVB Prostate Cancer AJCC v8 Triple-Negative Breast Carcinoma Unresectable Solid Neoplasm Collapse <<	Phase 1	Recruiting	April 1, 2021	United States, Colorado ... more >> University of Colorado Hospital Suspended Aurora, Colorado, United States, 80045 United States, Maryland Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting Baltimore, Maryland, United States, 21287 Contact: Site Public Contact    410-955-8804    jhcccro@jhmi.edu    Principal Investigator: Roisin M. Connolly          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Site Public Contact    212-639-7592       Principal Investigator: Alison M. Schram          United States, Texas M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Site Public Contact    877-312-3961       Principal Investigator: Jordi Rodon Ahnert Collapse <<

• 参考文献

• [1] Wee S, Wiederschain D, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13057-62.

  [2] Barlaam B, Cosulich S, et al. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem. 2015 Jan 22;58(2):943-62.

  [3] Hancox U, Cosulich S, et al. Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Mol Cancer Ther. 2015 Jan;14(1):48-58.