生物活性

• 靶点

  Akt1 IC50:3nM

  Akt2 IC50:8nM

  Akt3 IC50:8nM

• 描述AKT is the central node of PI3K/AKT/mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound^[1]. AK316078 is an ATP-competitive pan AKT inhibitor with IC50 values of 13, 66, 57 nM for AKT 1, 2 and 3 (measured by enzyme assays), respectively^[2]. AZD5363 on concentration of 0.3 – 10 μM effectively inhibited phosphorylation of S6 and 4E-BP1, which are the downstream of AKT, in LNCaP and BT474 cells, whereas it increased phosphorylation of AKT at both Ser473 and Thr308 like other ATP-competitive AKT inhibitors. Treatment with 3 μM AZD5363 for 2h can induce FOXO3a nuclear translocation. In cell growth inhibition assays, HER2⁺ and ER⁺ breast cancer cell lines showed most consistently sensitivity to AZD5363 (<3 μM). Oral administration of AZD5363 at 100 mg/kg twice daily resulted in 80% inhibition in HER2⁺ amplified, PIK3CA mutant BT474c xenografts. AZD5363 at 150 mg/kg twice daily caused pronounced tumor regression (129% inhibition), whereas 75 mg/kg twice daily resulted in 111% inhibition in HER2⁺ amplified, PIK3CA mutant HCC-1954 breast cancer xenograft^[3]. Several clinical trials of AZD5363, including a completed phase 2 study of treatment for invasive breast cancer, have been done (see in https://clinicaltrials.gov/).
• 作用机制AZD5363 is an ATP-competitive AKT inhibitor.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  1%MCF7	400 nM	Growth Inhibition Assay	6 d	increased drug sensitivity of 4-OHT and fulvestrant	26351323
  23132/87	-	Growth Inhibition Assay	-	IC50=1.671 μM	24088382
  AGS	-	Growth Inhibition Assay	-	IC50=0.552 μM	24088382

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• 动物研究
  剂量	Mice (p.o.): min = 50 mg/kg[4], max = 300 mg/kg[3]
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Administration i.v. i.v. i.v. T1/2 0.2 h 0.5 h 1.7 h Protein binding (free drug %) 14.3-16.7 23.5-25.1 19.2-22.9 Vdss 4.1 L/kg 4.0 L/kg 2.1 L/kg CL 207 ml/min/kg (blood Cl) 6 μl/min/106 cells (hepatocyte Clint) 95 ml/min/kg (blood Cl) 32 μl/min/106 cells (hepatocyte Clint) 22 ml/min/kg (blood Cl) 10 μl/min/106 cells (hepatocyte Clint) F 0.86 0.13 0.37

• 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
  NCT03742102	Triple Negative Breast Neoplas... more >>ms Collapse <<	Phase 1 Phase 2	Not yet recruiting	June 3, 2022	United States, Arizona ... more >> Research Site Not yet recruiting Goodyear, Arizona, United States, 85338 Research Site Not yet recruiting Tucson, Arizona, United States, 85712 United States, California Research Site Not yet recruiting Los Angeles, California, United States, 90048 United States, Florida Research Site Not yet recruiting New Port Richey, Florida, United States, 34653 United States, Georgia Research Site Not yet recruiting Newnan, Georgia, United States, 30265 United States, Illinois Research Site Not yet recruiting Zion, Illinois, United States, 60099 United States, Missouri Research Site Not yet recruiting Saint Louis, Missouri, United States, 63110 United States, Oklahoma Research Site Not yet recruiting Tulsa, Oklahoma, United States, 74133 United States, Pennsylvania Research Site Not yet recruiting Philadelphia, Pennsylvania, United States, 19124 United States, Utah Research Site Not yet recruiting Salt Lake City, Utah, United States, 84112 Korea, Republic of Research Site Not yet recruiting Seoul, Korea, Republic of, 03080 Research Site Not yet recruiting Seoul, Korea, Republic of, 05505 Research Site Not yet recruiting Seoul, Korea, Republic of, 06351 Taiwan Research Site Not yet recruiting Taichung, Taiwan, 40447 Research Site Not yet recruiting Taipei, Taiwan, 100 United Kingdom Research Site Not yet recruiting London, United Kingdom, EC1M 6BQ Research Site Not yet recruiting London, United Kingdom, W1T 7HA Research Site Not yet recruiting Manchester, United Kingdom Research Site Not yet recruiting Oxford, United Kingdom, OX3 7LE Research Site Not yet recruiting Truro, United Kingdom, TR1 3LJ Collapse <<
  NCT02465060	Advanced Malignant Solid Neopl... more >>asm Bladder Carcinoma Breast Carcinoma Cervical Carcinoma Colon Carcinoma Colorectal Carcinoma Endometrial Carcinoma Esophageal Carcinoma Gastric Carcinoma Glioma Head and Neck Carcinoma Kidney Carcinoma Liver and Intrahepatic Bile Duct Carcinoma Lung Carcinoma Lymphoma Malignant Uterine Neoplasm Melanoma Ovarian Carcinoma Pancreatic Carcinoma Plasma Cell Myeloma Prostate Carcinoma Rectal Carcinoma Recurrent Bladder Carcinoma Recurrent Breast Carcinoma Recurrent Cervical Carcinoma Recurrent Colon Carcinoma Recurrent Colorectal Carcinoma Recurrent Esophageal Carcinoma Recurrent Gastric Carcinoma Recurrent Glioma Recurrent Head and Neck Carcinoma Recurrent Liver Carcinoma Recurrent Lung Carcinoma Recurrent Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Melanoma Recurrent Ovarian Carcinoma Recurrent Pancreatic Carcinoma Recurrent Plasma Cell Myeloma Recurrent Prostate Carcinoma Recurrent Rectal Carcinoma Recurrent Skin Carcinoma Recurrent Thyroid Gland Carcinoma Recurrent Uterine Corpus Carcinoma Refractory Lymphoma Refractory Malignant Solid Neoplasm Refractory Plasma Cell Myeloma Skin Carcinoma Thyroid Gland Carcinoma Uterine Corpus Cancer Collapse <<	Phase 2	Recruiting	-	-
  NCT02664935	Non-Small Cell Lung Cancer ... more >> Carcinoma, Squamous Cell Adenocarcinoma Collapse <<	Phase 2	Recruiting	September 2021	United Kingdom ... more >> Belfast City Hospital, Belfast Health and Social Care Trust Recruiting Belfast, United Kingdom Contact: Paula Scullin          Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust Recruiting Birmingham, United Kingdom, B15 2GW Contact: Gary Middleton, MB BS MD FRCP          Principal Investigator: Gary Middleton, MB BS MD FRCP          Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust Recruiting Birmingham, United Kingdom Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust Recruiting Cambridge, United Kingdom, CB2 0QQ Contact: David Gilligan, BSc (Hons) MB BChir FRCP FRCR       cctc@addenbrookes.nhs.uk    Principal Investigator: David Gilligan, BSc (Hons) MB BChir FRCP FRCR          Velindre Cancer Centre, Velindre NHS Trust Recruiting Cardiff, United Kingdom, CF14 2TL Contact: Alison Brewster, BSC MB BCh FRCR MD    029 2061 5888       Principal Investigator: Alison Brewster, BSC MB BCh FRCR MD          Edinburgh Cancer Centre, Western General Hospital Recruiting Edinburgh, United Kingdom, EH4 2XU Contact: Melanie Mackean, MB ChB MRCP MSc MD          Principal Investigator: Melanie Mackean, MB ChB MRCP MSc MD          Royal Devon and Exeter Hospital Recruiting Exeter, United Kingdom Contact: Elizabeth Toy          Principal Investigator: Elizabeth Toy          Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre Recruiting Glasgow, United Kingdom, G12 0YN Contact: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST          Principal Investigator: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST          St. James' University Hospital, Leeds Teaching Hospital NHS Trust Recruiting Leeds, United Kingdom, LS9 7TF Contact: Clive Mulatero, BA MB BCh MA PhD FRCP          Principal Investigator: Clive Mulatero, BA MB BCh MA PhD FRCP          Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust Recruiting Leicester, United Kingdom Contact: Dean Fennell          Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust Recruiting London, United Kingdom, SW3 6JJ Contact: Sanjay Popat          Principal Investigator: Sanjay Popat, BSc MB BS MRCP PhD FRCP          Charing Cross Hospital, Imperial College Healthcare NHS Trust Recruiting London, United Kingdom Contact: Conrad Lewanski          Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust Recruiting London, United Kingdom Contact: James Spicer          St Bartholomew's Hospital, Barts Health NHS Trust Recruiting London, United Kingdom Contact: John Conibear          University College Hospital, University College London Hospitals NHS Foundation Trust Recruiting London, United Kingdom The Christie Hospital, The Christie NHS Foundation Trust Recruiting Manchester, United Kingdom Contact: Yvonne Summers          Sir Bobby Robson Cancer Trial Research Centre, The Newcastle upon Tyne Hospitals Recruiting Newcastle, United Kingdom, NE7 7DN Contact: Alastair Greystoke          Principal Investigator: Alastair Greystoke, BSc MBChB MRCP MSc PhD          Churchill Hospital, Oxford University Hospitals NHS Foundation Trust Recruiting Oxford, United Kingdom Contact: Denis Talbot          Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust Recruiting Sheffield, United Kingdom Contact: Sarah Danson          Southampton General Hospital, University Hospital Southampton NHS Foundation Trust Recruiting Southampton, United Kingdom, SO16 6YD Contact: Christian Ottensmeier       clinicaltrials@uhs.nhs.uk    Principal Investigator: Christian Ottensmeier Collapse <<

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• 参考文献

• [1] Huck BR, Mochalkin I, et al. Recent progress towards clinically relevant ATP-competitive Akt inhibitors. Bioorg Med Chem Lett. 2017 Jul 1;27(13):2838-2848.

  [2] Addie M, Ballard P, et al. Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem. 2013 Mar 14;56(5):2059-73.

  [3] Davies BR, Greenwood H, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012 Apr;11(4):873-87.

  [4] Searle EJ, Telfer BA, et al. Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment. EMBO Mol Med. 2017 Dec;9(12):1646-1659.