生物活性

• 靶点

  PI3Kα IC50:0.29nM

  PI3Kγ IC50:0.97nM

  PI3Kδ IC50:0.12nM

• 描述Phosphoinositide-3 kinase (PI3K) plays important role in response to various extracellular triggers and in activation of downstream Akt and mTOR, which together control the tumor cell proliferation. GDC-0032 is the inhibitor of PI3K with Ki of 0.29 nM for PI3Kα, with IC₅₀ values of 4.0 nM and 25 nM for p-Akt and MCF7-neo/HER2 cell lines respectively. In MCF7-neo/Her2 xenograft model, treatment of GDC-0032 with concentrations ranging from 1.4 to 22.5 mg/kg resulted in an increasing of tumor growth inhibition with corresponding inhibition rates from 19% to 123%, dose-dependently. Akt phosphorylation was also decreased by 59% when treated with 2.8 mg/kg of GDC-0032. In a panel containing 235 kinases, treated them with 1 μM GDC-0032 led to >70% inhibition in PI3K-C2 beta, PI3Kα, PI3Kδ, PI3Kγ and hVPS34. The IC₅₀ values for PI3K-C2 beta and hVPS34 were 292 nM and 374 nM, respectively^[1]. In a panel of 26 HNSCC cell lines, GDC-0032 showed gradient inhibition IC₅₀ values ranging from 0.05 to 2 μM. The 4 cell lines with IC₅₀ values 2 μM are most resistant to GDC-0032 due to the mutation or loss of PTEN gene. In Cal-33 cells harboring a PIK3CA H1047R mutation, treatment of GDC-0032 with concentrations ranging from 0 to 4 μM prevented AKT phosphorylation and inhibited S6 kinase level, leading to an induction of apoptosis. However, less effect on AKT/mTOR signaling in cell lines containing PTEN mutations was also observed, which means that GDC-0032 only inhibits PI3Kα-dependent signaling. Also in Cal-33 cells, the combination treatment of GDC-0032 and radiation led to more apoptotic, more non-apoptotic cell death and slower cell growth rates. In Cal-33 xenografts mice model with 5 mg/kg of GDC-0032, AKT and PRAS40 phosphorylation were almost completely abrogated as well as the decreasing of 4EBP-1 and S6 phosphorylation at 2 hours treatment. The treatment also mildly improved the proportion of cells in G1 phase and decreased G2 phase of the cell cycle over 72 hours^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human MOLM16 cells	-	Proliferation assay	72 h	Antiproliferative activity against human MOLM16 cells after 72 hrs by Cell Titer-Blue assay	22727640

• 动物研究
  剂量	Mice: 0.2 mg/kg - 25 mg/kg[3] (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
  NCT02154490	Recurrent Squamous Cell Lung C... more >>arcinoma Stage IV Squamous Cell Lung Carcinoma AJCC v7 Collapse <<	Phase 2 Phase 3	Recruiting	April 1, 2022	-
  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	-	-
  NCT02340221	Breast Cancer	Phase 3	Active, not recruiting	July 3, 2021	-

• 更多
• 参考文献

• [1] Ndubaku CO, Heffron TP, et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem. 2013;56(11):4597-610.

  [2] Zumsteg ZS, Morse N, et al. Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations. Clin Cancer Res. 2016;22(8):2009-19.