生物活性

• 描述Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer ^[3]. GDC-0084 is a brain penetrant inhibitor of PI3K and mTOR, with Kiapp values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively ^[4]. GDC-0084 maintains inhibition of each of the Class I PI3K isoforms but with more potent inhibition of mTOR. GDC-0084 is also tested in five different GBM (glioblastoma multiforme) cell lines and is found to have antiproliferative EC50s ranging from 0.3 to 1.1 Μm ^[4]. After a 25 mg/kg dose of GDC-0084 administered orally, pAKT in normal mouse brain tissue is significantly inhibited at 1 and 6 h postdose. The potent inhibition of pAKT at both time points in this study demonstrates that GDC-0084 inhibits its target behind a fully intact BBB (blood-brain barrier). In addition to the pharmacodynamic effect in normal brain tissue, GDC-0084 is studied in a subcutaneous U87 tumor xenograft model of glioblastoma in mice. In this study, GDC-0084 achieves significant and dose-dependent tumor growth inhibition. Tumor growth inhibition is first observed at a 2.2 mg/kg dose level. Higher doses led to greater tumor growth inhibition, including tumor regressions at the 17.9 mg/kg dose level. Each of these doses is well tolerated for the duration of the study ^[4].
• 作用机制GDC-0084 is a brain penetrant inhibitor of PI3K and mTOR.
• 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
  NCT01547546	Glioblastoma, Glioma	Phase 1	Completed	-	United States, California ... more >> Los Angeles, California, United States, 90095 United States, Massachusetts Boston, Massachusetts, United States, 02114 Boston, Massachusetts, United States, 02115 United States, Texas Houston, Texas, United States, 77030 Spain Barcelona, Spain, 08035 Collapse <<
  NCT03696355	Brain and Central Nervous Syst... more >>em Tumors Collapse <<	Phase 1	Recruiting	June 2024	United States, Tennessee ... more >> St. Jude Children's Research Hospital Recruiting Memphis, Tennessee, United States, 38105 Contact: Tabatha E. Doyle, RN    901-595-2544    tabatha.doyle@stjude.org    Principal Investigator: Christopher Tinkle, MD, PhD          Principal Investigator: Amar Gajjar, MD Collapse <<
  NCT03765983	Breast Cancer	Phase 2	Not yet recruiting	November 30, 2025	United States, Massachusetts ... more >> Dana Farber Cancer Institute Not yet recruiting Boston, Massachusetts, United States, 02215 Contact: Jose P Leone, MD    617-632-3548    JoseP_Leone@dfci.harvard.edu    Principal Investigator: Jose P Leone, MD Collapse <<

• 更多
• 参考文献

• [1] Salphati L, Alicke B, et al. Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma. Drug Metab Dispos. 2016 Dec;44(12):1881-1889.

  [2] Heffron TP, Ndubaku CO, et al. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med Chem Lett. 2016 Feb 16;7(4):351-6.

  [3] Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in Human Disease. Cell. 2017 Aug 10;170(4):605-635. doi: 10.1016/j.cell.2017.07.029. PMID: 28802037; PMCID: PMC5726441.

  [4] Heffron TP, Ndubaku CO, Salphati L, Alicke B, Cheong J, Drobnick J, Edgar K, Gould SE, Lee LB, Lesnick JD, Lewis C, Nonomiya J, Pang J, Plise EG, Sideris S, Wallin J, Wang L, Zhang X, Olivero AG. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med Chem Lett. 2016 Feb 16;7(4):351-6. doi: 10.1021/acsmedchemlett.6b00005. PMID: 27096040; PMCID: PMC4834666.