ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

Kong, Dexin; Yamori, Takao

doi:10.1038/aps.2010.150

Cited by 65 publications

(53 citation statements)

References 74 publications

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“…In summary, inhibiting the PI3K-AktmTOR pathway can prevent TM-induced ER stress. There was no significant difference in inhibition caused by rapamycin and NVP-BEZ235 treatment, This result might have been due to the competitive inhibition effect of NVP-BEZ235, an observation consistent with that of Kong and Yamori (2010) who reported that NVP-BEZ235 and ATP were competitive inhibitors of mTOR and PI3K, but caused more reactive inhibition of mTOR. but the inhibition resulting from the treatment with LY294002 was significantly different.…”

Section: Discussionsupporting

confidence: 85%

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

et al. 2016

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ABSTRACT. PI3K-Akt-mTOR signaling pathway is associated with endoplasmic reticulum (ER) stress. However, it is not clear how this signaling pathway affects the ER stress. The present study aimed to determine whether the PI3K-Akt-mTOR signaling pathway regulates tunicamycin (TM)-induced increases in mRNA levels of genes involved in the ER stress, to help elucidate the mechanism by which this pathway affects the ER stress in primary goose hepatocytes. Primary hepatocytes were isolated from geese and cultured in vitro. After 12 h in a serumfree medium, the hepatocytes were incubated for 24 h in a medium with either no addition (control) or with supplementation of TM or TM together with PI3K-Akt-mTOR signaling pathway inhibitors (LY294002, rapamycin, NVP-BEZ235). Thereafter, the expression levels of genes involved in the ER stress (BIP, EIF2a, ATF6, and XBP1) were assessed. The results indicated that the mRNA level of BIP 2 Q. Song et al. Genetics and Molecular Research 15 (3): gmr.15037868 was up-regulated in 0.2, 2, and 20 µM TM treatment group (P < 0.05), whereas the mRNA levels of EIF2a, ATF6, and XBP1 were up-regulated in the 2 µM TM treatment group (P < 0.05). However, the TM mediated induction of mRNA levels of genes involved in the ER stress (BIP, EIF2a, ATF6, and XBP1) was down-regulated after the treatment with PI3K-Akt-mTOR pathway inhibitors (LY294002, NVP-BEZ235, and rapamycin). Therefore, our results strongly suggest that the PI3K-AktmTOR signaling pathway might be involved in the down-regulation of the TM-induced ER stress in primary goose hepatocytes.

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Section: Discussionsupporting

confidence: 85%

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

et al. 2016

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“…With multiple efforts under way in academia and industry to develop clinically relevant inhibitors against PI3K, a number of inhibitors have entered clinical trials, including PI3K selective inhibitors (either isoform-specific or pan-class I PI3K inhibitors) and dual PI3K/mTOR inhibitors (Pal and Mandal, 2012). Among them, dual PI3K/mTOR inhibitors target both PI3K and mTOR and avoid reactivation of PI3K induced by mTOR inhibition (Li et al, 2010), pan-PI3K inhibitors target all isoforms of class I PI3Ka (Kong and Yamori, 2010), and isoform-specific PI3K inhibitors preferentially target one isoform of class I (Engelman, 2009). Although most drug candidates now in clinical trials are pan-PI3K inhibitors or dual PI3K/mTOR inhibitors, generation of more selective agents is supposed to be advantageous to reduce side effects.…”

Section: Introductionmentioning

confidence: 99%

DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110α (H1047R)

Liu

Gao

Zhang

et al. 2013

J Pharmacol Exp Ther

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Phosphatidylinositol 3-kinase, a isoform (PI3Ka) plays essential roles in cell metabolism, growth, and proliferation and has been validated as a promising anticancer target. In an effort to search for new PI3Ka-selective inhibitors, DW series compounds were designed and synthesized aiming to reduce the off-target effects of their parent compound PIK-75 [2-methyl-5-nitro-1-benzenesulfonic acid 2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide], which was reported to selectively target PI3Ka. A series of compounds named DW series potently inhibited the kinase activity of PI3Ka with little activity against PI3K-related protein kinases and a panel of 15 tyrosine kinases. Similar to PIK-75, DW series compounds were more potent to inhibit PI3Ka among four class I PI3K isoforms, whereas a representative compound DW09849 [(E)-N9-((6-bromoimidazo[1,2-a] pyridin-3-yl)methylene)-N-ethyl-2-methyl-5-nitrobenzohydrazide] displayed distinct binding mode compared with PIK-75. Although DW series compounds inhibited proliferation of rhabdomyosarcoma RH30 cells at elevated 50% inhibitory concentrations (IC 50 ) in comparison with PIK-75, they were more selective than PIK-75 to inhibit PI3K signaling in the cellular context. In particular, DW09849 significantly and persistently blocked PI3K/protein kinase B signaling in RH30 cells, which consequently arrested RH30 cells in the G 1 phase. Moreover, DW09849 selectively suppressed the proliferation and clonogenesis of transformed RK3E/HR cells harboring oncogenic mutation of p110a H1047R, as well as a panel of human breast cancer cells containing mutated PI3Ka, which is consistent with the finding that DW09849 demonstrated preference against H1047R mutated PI3Ka in molecular docking stimulation. These results suggest that DW series compounds, especially DW09849, selectively targeting PI3Ka with less off-target effects than PIK-75, provide new clues for the design and discovery of new specific PI3Ka inhibitors for cancer therapy.

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“…PI3K has been validated as a therapeutic tumor target of increasing interest from the research community of tumor biology and cancer therapeutics as well [8,9] . Due to efforts in academia and industry to develop clinically relevant inhibitors, a number of pan-or isoform-specific PI3K inhibitors have been identified and developed as potential molecularly targeted anticancer therapies, including GDC0941 (pan-PI3K), A66 (PI3Kα), TGX221 (PI3Kβ), AS604850 (PI3Kγ), and CAL-101 (PI3Kδ) [6,[10][11][12][13][14] . Isoform inhibitors may enhance targeting and reduce toxicity, whereas pan-PI3K inhibitors are thought to be more potent with wide antitumor spectrum.…”

Section: Introductionmentioning

confidence: 99%

A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth

Wei

Yang

et al. 2013

Acta Pharmacol Sin

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Aim: To identify the contribution of individual isoform (α, β, γ, δ) of class I PI3Ks to tumor cell growth for proper use of PI3K inhibitors in cancer therapy. Methods: A panel of human rhabdomyosarcoma Rh30 cells stably expressing myristoylation (Myr)-tagged one of class I PI3K p110 subunits was established. PI3K activity was analyzed by measuring phosphorylated Akt with Western blotting, and isoform-specific PI3K activities were validated with PI3K isoform-selective inhibitors. The growth of prostate cancer PC-3 cells and B cell type leukemia Raji cells was determined using SRB assay and CCK-8 assay, respectively. Results: The phosphorylation of Akt in Rh30-Myr-p110α, β, γ, δ cells was preferentially inhibited by PI3K isoform-selective inhibitors A66 (PI3Kα), TGX221 (PI3Kβ), AS604850 (PI3Kγ) and CAL-101 (PI3Kδ), respectively. A newly obtained PI3K inhibitor WJD008 (10 μmol/L) completely abrogated Akt phosphorylation by all the isoforms of class I PI3Ks, thus acted as a pan-PI3K inhibitor. In prostate cancer PC-3 cells, the PI3K isoform-selective inhibitors were much less potent than WJD008 in suppression of the proliferation. In B cell type leukemia Raji cells, inhibition of PI3Kδ alone or all the isoforms of class I PI3Ks displayed similar potency against the cell proliferation, whereas selective inhibition of individual PI3Kα/β/γ isoforms resulted in negligible activity. Conclusion: Rh30-Myr-p110α, β, γ, δ cells are a useful cell model to identify the selectivity of PI3K inhibitors. Pan-PI3K inhibitors are suitable for treating PC-3 cells, whereas selective PI3Kδ inhibitor is sufficient to block Raji cell growth. The biased dependency on PI3K isoforms for tumor cell growth rationalizes the use of PI3K inhibitors with different selectivity for cancer therapy.

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ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

Cited by 65 publications

References 74 publications

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110α (H1047R)

A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth

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