生物活性

• 靶点

  PI3Kα IC50:5nM

  PI3Kβ IC50:27nM

  PI3Kγ IC50:14nM

  PI3Kδ IC50:7nM

• 描述PI3K and mTOR are two critical signaling pathways that of high degree similarity of active sites and thus are important for cell growth and cancer treatment. GDC-0980 is a class 1 PI3K and mTOR kinase inhibitor with IC50 values of 5, 27, 7 and 14 nM for PI3Kα, β, δ and γ isoforms respectively. The Ki of GDC-0980 against mTOR is 17nM. Treatment with 1 μM GDC-0980 could also show >60% inhibition to some additional kinases like Fgr, Mlk1, Syk with IC50 VALUES of 697, 232, 134 nM respectively. In PC-3 and MCF-7 neo/HER2 cell lines, treatment with 1 mg/kg of this drug demonstrated significant antitumor activity and tumor growth delay. Tumor stasis or regressions were also observed with the concentration of 7.5 mg/kg, which further showed a high cellular potency and low plasma clearance^[1]. Treatment of GDC-0980 with IC50 <500nM demonstrated 100%, 78%, 88%, 67% and 33% inhibitions to prostate, breast, NSCLC, pancreatic and melanoma cell lines respectively, suggesting different reduction of viability in alternated cancer cells. Furthermore, phosphorylation of all downstream markers was reduced including phospho-Akt (at Thr308, Ser473 sites), phospho-S6 and phospho-ERK. The assessment results of cell cycle markers treated with 0.1 and 0.5 μM GDC-0980 found that Cyclin D1 expressed in most proliferating cells except for KP4 and A375 cell lines. Besides, cleaved PARP was also found in KPL4 and LoVo cell lines, suggesting an earlier apoptotic response to this drug. In a 20 xenograft tumor models, treatment of 5 mg/kg GDC-0980 resulted in 70% loss of body weight and 50% tumor growth inhibitions in 15 of the models. In pharmacokinetic mice model, 2.5 mg/kg of GDC-0980 could delay tumor growth. Tumor stasis and tumor regression were happened at higher concentrations that were 5 mg/kg and 10 mg/kg respectively. In the 2.5 mg/kg concentration group, undetectable GDC-0980 plasma levels was found as well as reduced baseline level of pAkt/tAkt that were 60% and 75% at 5 and 10 mg/kg concentration groups, suggesting GDC-0980 is an effective dual PI3K/mTOR inhibitor^[2].
• 作用机制GDC-0980 binds to mTORC1 and mTORC2, decreasing phospho-AktThr308 and Ser473, S6K and phospho-S6^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human MCF7.1 cells	-	Proliferation assay	-	Antiproliferative activity against human MCF7.1 cells expressing HER2 gene after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.255 μM	21981714
  human PC3 cells	-	Function assay	-	Inhibition of PIK3 gamma-mediated Akt phosphorylation at Ser473 in human PC3 cells by ELISA, IC50=0.036 μM	21981714
  human PC3 cells	-	Proliferation assay	-	Antiproliferative activity against human PC3 cells after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.307 μM	21981714

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• 动物研究
  剂量	Mice: 0.25 mg/kg - 10 mg/kg[2] (p.o.)
  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
  NCT01301716	Solid Cancers	Phase 1	Completed	-	United States, California ... more >> Los Angeles, California, United States, 90025 United States, Florida Tampa, Florida, United States, 33612 United States, Massachusetts Boston, Massachusetts, United States, 02114 Boston, Massachusetts, United States, 02215 Spain Madrid, Spain, 28050 Collapse <<
  NCT01485861	Prostate Cancer	Phase 1 Phase 2	Active, not recruiting	July 31, 2019	-
  NCT01332604	Solid Cancers	Phase 1	Completed	-	United States, California ... more >> Los Angeles, California, United States, 90095 United States, Colorado Aurora, Colorado, United States, 80045 United States, Minnesota Rochester, Minnesota, United States, 55905 Spain Barcelona, Spain, 08035 Collapse <<

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• 参考文献

• [1] Sutherlin DP, Bao L, et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem. 2011;54(21):7579-87.

  [2] Wallin JJ, Edgar KA, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011;10(12):2426-36.