Isoform-Selective Inhibition of Phosphoinositide 3-Kinase: Identification of a New Region of Nonconserved Amino Acids Critical for p110α Inhibition

Zheng, Zhihai; Amran, Syazwani Itri; Thompson, Phillip E.; Jennings, Ian G.

doi:10.1124/mol.111.072546

Cited by 38 publications

(46 citation statements)

References 25 publications

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“…The PI3K pathway regulates cellular functions relevant to tumourogenesis, but unfortunately, clinical studies of broad PI3K inhibitors have been plagued by toxicity (Zheng et al, 2011). More specific approaches to inhibit specific isoforms in MM were performed; PI3KCD was inhibited using the specific inhibitor CAL-101, which overcame MM cell growth conferred by IL6, IGF1, and bone marrow stromal cell coculture .…”

Section: Discussionmentioning

confidence: 99%

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

Azab

Vali²,

Abraham

et al. 2014

Br J Haematol

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SummaryThe phosphatidylinositide 3-kinase (PI3K) pathway is activated and correlated with drug resistance in multiple myeloma (MM). In the present study we investigated the role of PI3KCA (PI3K-a) in the progression and drug resistance in MM. We showed that the gene expression of PI3KCA isoform was higher in MM compared to normal subjects. BYL719, a novel and specific PI3KCA inhibitor inhibited the survival of primary MM cells and cell lines but not normal peripheral blood mononuclear cells. BYL719 induced the apoptosis of MM cells and inhibited their cell cycle by causing G1 arrest. BYL719 inhibited PI3K signalling, decreased proliferation and cells cycle signalling, and induced apoptosis signalling in MM cells. Finally, BYL719 synergized with bortezomib and carfilzomib, and overcame drug resistance induced by bone marrow stroma. These results were confirmed using in silico simulation of MM cell lines, BYL719 and bortezomib, and showed similar trends in survival, proliferation, apoptosis, cell signalling and synergy with drugs. In conclusion, PI3KCA plays a major role in proliferation and drug resistance of MM cells, the effects of which were inhibited with BYL719. These results provide a preclinical basis for a future clinical trial of BYL719 in MM as a single agent or in combination with other drugs.

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Section: Discussionmentioning

confidence: 99%

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

Azab

Vali²,

Abraham

et al. 2014

Br J Haematol

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“…Only 2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid (PIK-75; refs. 23,24) and NCGC00012848-02 (NIH-12848; ref. 25) have been identified as substrate-competitive inhibitors.…”

Section: Introductionmentioning

confidence: 99%

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

Gao

Zhao

et al. 2017

Cancer Research

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While phosphatidylinositol 4-kinase (PI4KIIa) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIa are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIa. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIa kinase activity (IC 50 ¼ 0.47 mmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIa. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIa knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIa. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIa. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G 2 -M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substratecompetitive, subtype-specific inhibitor of PI4KIIa, the use of which will facilitate evaluations of PI4KIIa as a cancer therapeutic target. Cancer Res; 77(22); 6253-66. Ó2017 AACR.

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“…MD simulation and its subsequent studies provided valuable tools for the development of isoform-specific PI3K inhibitors, complementing the molecular modeling method [151]. It has been reported that the combinatory effort of comparative molecular field analysis (CoMFA), comparative molecular similarity induces analysis (CoMSIA), docking analysis and MD simulation can elucidate the structure-activity correlation of the inhibitors of p110α, as well as the binding modes of inhibitors at the ATP binding pocket [152].…”

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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Isoform-Selective Inhibition of Phosphoinositide 3-Kinase: Identification of a New Region of Nonconserved Amino Acids Critical for p110α Inhibition

Cited by 38 publications

References 25 publications

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

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

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