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

Liu, Jiali; Gao, Guofu; Zhang, Xi; Cao, Sufen; Guo, Chen-liang; Wang, Xiang; Tong, Linjiang; Ding, Jian; Duan, Wenhu; Meng, Linghua

doi:10.1124/jpet.113.210724

Cited by 13 publications

(3 citation statements)

References 34 publications

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“…The PI3Kα inhibitor treatment results in G 1 phase arrest without killing cells in vitro [7] , which is consistent with lack of tumor regression in clinical settings. Sporadic studies have indicated the induction of apoptosis by NVP-BYL719, but this effect appears to be dependent on cell types [8] .…”

Section: Pi3kα-selective Inhibitorssupporting

confidence: 70%

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies

2015

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The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin's lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents.

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Section: Pi3kα-selective Inhibitorssupporting

confidence: 70%

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies

2015

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“…Recombinant protein was extracted by affinity purification. The PI3K kinase activity was determined in the increasing concentration of ATP and X-370 with PI3-Kinase HTRF™ Assay kit (Millipore) as described previously [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia

Wang

Zhang

et al. 2014

Oncotarget

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B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.

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“…Encouragingly, an in silico docking and MD simulation study of 33 PI3K inhibitors binding to conformations of the wild-type and mutant PI3Kα has demonstrated the conformation differences between an H1047 mutation and wild-type p110α for mutant-PI3Kα-specific drug design [161]. Other studies using structure-based drug design led to the development of mutated-PI3Kα targeted inhibitors, such as CH5132799 and DW09849 [162,163]. The drug efficacy of such new-generation inhibitors is in the process of characterization.…”

Section: Molecular Dynamics Simulation Inspires a New Generation Omentioning

confidence: 99%

Computer-Aided Targeting of the PI3K/Akt/mTOR Pathway: Toxicity Reduction and Therapeutic Opportunities

Tan

Wang

2014

IJMS

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The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead to complications, such as tumorigenesis, type 2 diabetes and cardiovascular diseases. Molecular targeted therapy, aimed at modulating the deregulated pathway, holds great promise for controlling these diseases, though side effects may be inevitable, given the ubiquity of the pathway in cell functions. Here, we review a variety of factors found to modulate the PI3K/Akt/mTOR pathway, including gene mutations, certain metabolites, inflammatory factors, chemical toxicants, drugs found to rectify the pathway, as well as viruses that hijack the pathway for their own synthetic purposes. Furthermore, this evidence of PI3K/Akt/mTOR pathway alteration and related pathogenesis has inspired the exploration of computer-aided targeting of this pathway to optimize therapeutic strategies. Herein, we discuss several possible options, using computer-aided targeting, to reduce the toxicity of molecularly-targeted therapy, including mathematical modeling, to reveal system-level control mechanisms and to confer a low-dosage combination therapy, the potential of PP2A as a therapeutic target, the formulation of parameters to identify patients who would most benefit from specific targeted therapies and molecular dynamics simulations and docking studies to discover drugs that are isoform specific or mutation selective so as to avoid undesired broad inhibitions. We hope this review will stimulate novel ideas for pharmaceutical discovery and deepen our understanding of curability and toxicity by targeting the PI3K/Akt/mTOR pathway.

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

Cited by 13 publications

References 34 publications

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies

Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia

Computer-Aided Targeting of the PI3K/Akt/mTOR Pathway: Toxicity Reduction and Therapeutic Opportunities

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