WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant

doi:10.1124/jpet.110.167940

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	WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant
	Li, Ting 1; Wang, Jia2 ; Wang, Xiang 1; Yang, Na 1; Chen, Si-meng 1; Tong, Lin-jiang 1; Yang, Chun-hao2 ; Meng, Ling-hua1 ; Ding, Jian1
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2010-09
卷号	334 期号:3 页码:830-838
ISSN号	0022-3565
DOI	10.1124/jpet.110.167940
文献子类	Article
英文摘要	The phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway is often constitutively activated in various human cancers, providing validated targets for cancer therapy. Among a series of 5-cyano-6-morpholino-4-substituted-pyrimidine analogs designed and synthesized based on PI3K target, 4-(2-(dimethylamino)vinyl)-2-(3-hydroxyphenyl)-6-morpholinopyrimidine-5-carbonitrile (WJD008) was selected for further pharmacological characterization because of its potent activity against PI3K signaling. WJD008 inhibited kinase activity of PI3K alpha and mTOR with less activity against PIKK family members. In cellular settings, WJD008 abrogated insulin-like growth factor-I-activated PI3K-Akt-mTOR signaling cascade and blocked the membrane translocation of a pleckstrin homology domain containing enhanced green fluorescent protein-general receptor for phosphoinositides, isoform 1-pleckstrin homology fusion protein, suggesting down-regulation of phosphatidylinositol (3,4,5)-trisphosphate output induced by WJD008 resulted in inactivation of PI3K pathway. Consequently, WJD008 arrested cells in G 1 phase without induction of apoptosis. Furthermore, WJD008 reversed the hyperactivation of the PI3K pathway caused by the oncogenic mutation of p110 alpha H1047R and suppressed the proliferation and clonogenesis of transformed RK3E cells harboring this mutant. WJD008 was superior to the pan-PI3K inhibitor wortmannin against proliferation of a panel of cancer cells independently of their status of PI3K pathway or tissue originations. In summary, WJD008 is a potent dual PI3K/mTOR modulator with antiproliferative and anticlonogenic activity in tumor cells and transformed cells with PIK3CA mutant, which provides new clues for the design and development of this chemical scaffold as an anticancer drug.
资助项目	National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2009ZX09301-001] ; Chinese Academy of Sciences[KSCX2-YW-R-25] ; National Natural Science Foundation of China[30721005] ; National Natural Science Foundation of China[90713034] ; Science and Technology Commission of Shanghai Municipality Pujiang[08PJ14114] ; Science and Technology Commission of Shanghai Municipality Pujiang[07dz05906] ; Science and Technology Commission of Shanghai Municipality Pujiang[09JC1416600]
WOS关键词	KINASE P110-ALPHA INHIBITORS ; DEPENDENT PROTEIN-KINASE ; GROWTH-FACTOR RECEPTOR ; ANTITUMOR-ACTIVITY ; IN-VIVO ; PHOSPHOINOSITIDE 3-KINASE ; BIOLOGICAL EVALUATION ; CANCER-CELLS ; PIK3CA GENE ; MUTATIONS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000281114900016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278789]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室国家新药筛选中心
通讯作者	Ding, Jian
作者单位	1.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Div Organ Synth, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Ting,Wang, Jia,Wang, Xiang,et al. WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2010,334(3):830-838.
APA	Li, Ting.,Wang, Jia.,Wang, Xiang.,Yang, Na.,Chen, Si-meng.,...&Ding, Jian.(2010).WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,334(3),830-838.
MLA	Li, Ting,et al."WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 334.3(2010):830-838.