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GDC-0084

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Chemical Structure| 1382979-44-3 同义名 : Paxalisib;RG7666
CAS号 : 1382979-44-3
货号 : A374932
分子式 : C18H22N8O2
纯度 : 99%+
分子量 : 382.42
MDL号 : MFCD30187522
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 : -
动物实验配方：
生物活性
靶点

  • p110γ

    PI3Kγ, Ki app:10 nM

  • p110β

    PI3Kβ, Ki app:46 nM

  • p110α

    PI3Kα, Ki app:2 nM

  • p110δ

    PI3Kδ, Ki app:3 nM
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.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.61mL

0.52mL

0.26mL

13.07mL

2.61mL

1.31mL

26.15mL

5.23mL

2.61mL
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.