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

Abstract

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␣ 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␣ 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.

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

“…The Grp1-PH domain is shown a specific binding affinity to PtdIns(3,4,5)P 3 rather than phosphatidylinositol 4,5-bisphosphate in cells and aggregates around the cell membrane responding to the recruitment of PtdIns(3,4,5)P 3 (15). As shown in Fig.…”

“…To further verify that phosphorylation of Akt and S6K1 is resulted from activation of PI3K in gastric cancer cells, the redistribution of the Grp1-PH domain after stimulation of CXCL12 was determined in CHO-K1 cells expressing Grp1-PH fused to EGFP (15). The Grp1-PH domain is shown a specific binding affinity to PtdIns(3,4,5)P 3 rather than phosphatidylinositol 4,5-bisphosphate in cells and aggregates around the cell membrane responding to the recruitment of PtdIns(3,4,5)P 3 (15).…”

ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

“…The vinyl pyrimidine core of ENMD-2076 is unique amongst Aurora kinase inhibitors; although, it is a property of the structures of other compounds inhibiting targets such as Tie-2 (31), Src and Abl (32), phosphatidylinositol 3-kinase and mTOR (33). Relative to other clinical stage Aurora kinase inhibitors, ENMD-2076 is most similar structurally to tozasertib (VX-680/MK0457; ref.…”

Translation Regulation as a Therapeutic Target in Cancer

“…In addition, the rapalog-insensitive mTORC2 complex phosphorylates the AKT hydrophobic motif and further enhances AKT activity. In an attempt to overcome resistance pathways, investigators have developed mTORC1/2 inhibitors (e.g., PP242, WYE-132, Torin1, AZD8055, OSI-027, and INK128) and inhibitors targeting mTORC1/2 and PI3K (e.g., PI-103, NVP-BEZ235, WJD008, and GSK2126458), and these agents have shown antitumor activity superior to that of rapalogs in various in vivo and in vitro cancer models, including lymphoma, leukemia, glioma, breast, lung, and renal carcinoma (110)(111)(112)(113)(114)(115)(116)(117)(118)(119). mTORC1/2 inhibitors (e.g., PP242) were more efficient in the inhibition of global protein synthesis and in eIF4F complex formation than rapamycin, illustrating the more-effective approach of targeting cap-dependent translation in cancer (120).…”