RT Journal Article
SR Electronic
T1 WJD008, a Dual PI3K/mTOR inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K mutant
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.110.167940
DO 10.1124/jpet.110.167940
A1 Ting Li
A1 Wang Jia
A1 Xiang Wang
A1 Na Yang
A1 Si-meng Chen
A1 Lin-Jiang Tong
A1 Chun-hao Yang
A1 Ling-hua Meng
A1 Jian Ding
YR 2010
UL http://jpet.aspetjournals.org/content/early/2010/06/03/jpet.110.167940.abstract
AB The phosphatidylinositol-3-kinase (PI3K)-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 analogues designed and synthesized based on PI3K target, WJD008 was selected for further pharmacological characterization due to its potent activity against PI3K signaling. WJD008 inhibited kinase activity of PI3Kα and mTOR with a pan-inhibitory activity against PIKK family members. In cellular sittings, WJD008 abrogated IGF-I-activated PI3K-Akt-mTOR signaling cascade and blocked the membrane translocation of a pleckstrin homology domain containing EGFP-Grp1-PH fusion protein, suggesting the downregulation of PtdIns(3,4,5)P3 output induced by WJD008 resulted in inactivation of PI3K pathway. Consequently, WJD008 arrested cells in G1 phase without induction of apoptosis. Furthermore, WJD008 reversed the hyperactivation of the PI3K pathway caused by the oncogenic mutation of p110α 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 independent 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 as well as transformed cells with PIK3CA mutant, which provides new clues for design and development of this chemical scaffold as anticancer drug.The American Society for Pharmacology and Experimental Therapeutics