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  1. Article ; Online: Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy.

    Kong, Dexin / Yamori, Takao

    Cancer science

    2008  Volume 99, Issue 9, Page(s) 1734–1740

    Abstract: ... for cancer therapy. During the last 5 years, several specific PI3K inhibitors were developed that were ... Phosphatidylinositol 3-kinases (PI3K) are a group of lipid kinases that phosphorylate ... phosphoinositides at the 3-hydroxyl group of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate ...

    Abstract Phosphatidylinositol 3-kinases (PI3K) are a group of lipid kinases that phosphorylate phosphoinositides at the 3-hydroxyl group of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate, a second messenger with key roles in fundamental cellular responses such as cell proliferation and metabolism. Frequent mutations found in or amplification of the PIK3CA gene and loss of phosphatase and tensin homolog deleted on chromosome 10 function in human tumors suggest that PI3K is a potential target for cancer therapy. During the last 5 years, several specific PI3K inhibitors were developed that were directed against various diseases. Some of them revealed potent anticancer efficacy and are now undergoing clinical trials. Some PI3K inhibitors showed antiangiogenic effects. Combined use of PI3K inhibitors with other chemotherapeutic agents or with radiotherapy produced synergistic therapeutic efficacies in treating cancer and showed reduced side effects. The rapid progress made in developing novel PI3K inhibitors in recent years promises bright prospects for finding a PI3K-targeted anticancer drug in the near future.
    MeSH term(s) Androstadienes/pharmacology ; Androstadienes/therapeutic use ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Proliferation/drug effects ; Chromones/pharmacology ; Chromones/therapeutic use ; Combined Modality Therapy ; Humans ; Morpholines/pharmacology ; Morpholines/therapeutic use ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Isoforms ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Androstadienes ; Angiogenesis Inhibitors ; Antineoplastic Agents ; Chromones ; Morpholines ; Protein Isoforms ; Protein Kinase Inhibitors ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; wortmannin (XVA4O219QW)
    Language English
    Publishing date 2008-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1349-7006
    ISSN (online) 1349-7006
    DOI 10.1111/j.1349-7006.2008.00891.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin's Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles.

    Ali, Abdalrahim M / Makki, Alaa A / Ibraheem, Walaa / Abdelrahman, Mohammed / Osman, Wadah / Sherif, Asmaa E / Ashour, Ahmed / Ibrahim, Sabrin R M / Ghazawi, Kholoud F / Samman, Waad A / Alzain, Abdulrahim A

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 5

    Abstract: ... to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin ... lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials ... good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising ...

    Abstract Non-Hodgkin's lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin's lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin's lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between -7.66 and -8.42 Kcal/mol. The docking analysis of ligand-receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with -52.22 Kcal/mol. To identify the structural changes and the complexes' stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand-protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with -29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.
    MeSH term(s) Humans ; Phosphoinositide-3 Kinase Inhibitors ; Phosphatidylinositol 3-Kinases ; Molecular Dynamics Simulation ; Gold/therapeutic use ; Molecular Docking Simulation ; Proto-Oncogene Proteins c-akt ; Ligands ; Density Functional Theory ; Metal Nanoparticles ; Lymphoma, Non-Hodgkin/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
    Chemical Substances Phosphoinositide-3 Kinase Inhibitors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Gold (7440-57-5) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Ligands
    Language English
    Publishing date 2023-03-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28052289
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  3. Article ; Online: Phosphatidylinositol 3-kinase isoforms as novel drug targets.

    Błajecka, Karolina / Borgström, Anna / Arcaro, Alexandre

    Current drug targets

    2011  Volume 12, Issue 7, Page(s) 1056–1081

    Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are key molecules in the signal transduction pathways ... we will describe the drugs currently used in clinical trials, as well as promising emerging candidates. ... an effective anti-cancer therapy may be difficult. The biggest challenge in curing cancer patients with various ...

    Abstract Phosphatidylinositol 3-kinases (PI3Ks) are key molecules in the signal transduction pathways initiated by the binding of extracellular signals to their cell surface receptors. The PI3K family of enzymes comprises eight catalytic isoforms subdivided into three classes and control a variety of cellular processes including proliferation, growth, apoptosis, migration and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer, but is also involved in other commonly occurring diseases such as chronic inflammation, autoimmunity, allergy, atherosclerosis, cardiovascular and metabolic diseases. The fact that the PI3K pathway is deregulated in a large number of human diseases, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. However, due to the complexity of PI3K signaling pathways, developing an effective anti-cancer therapy may be difficult. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments. In this article we will give an overview of the complex role of PI3K isoforms in human diseases and discuss their potential as drug targets. In addition, we will describe the drugs currently used in clinical trials, as well as promising emerging candidates.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Drug Delivery Systems ; Drug Design ; Enzyme Inhibitors/pharmacology ; Humans ; Isoenzymes ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/drug effects
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Isoenzymes ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2011-01-26
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2064859-5
    ISSN 1873-5592 ; 1389-4501
    ISSN (online) 1873-5592
    ISSN 1389-4501
    DOI 10.2174/138945011795677773
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5578: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Development of an immunohistochemical protein quantification system in conjunction with tissue microarray technology for identifying predictive biomarkers for phosphatidylinositol 3-kinase inhibitors.

    Isoyama, Sho / Yoshimi, Hisashi / Dan, Shingo / Okamura, Mutsumi / Seki, Mariko / Irimura, Tatsuro / Yamori, Takao

    Biological & pharmaceutical bulletin

    2012  Volume 35, Issue 9, Page(s) 1607–1613

    Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers by gain ... target for cancer therapy. Many agents targeting PI3K have been developed and some of them have been ... of-function mutations of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) or dysfunction ...

    Abstract The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers by gain-of-function mutations of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) or dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Therefore PI3K is thought to be a promising target for cancer therapy. Many agents targeting PI3K have been developed and some of them have been evaluated in clinical trials. In recent years, development of predictive biomarkers as companion diagnostics for molecular targeted drugs has become an important requirement for clinical development; however, no clinically established biomarkers that predict the efficacy of PI3K inhibitors have been found. We previously reported that expression of phosphorylated Akt determined by immunoblot analysis correlated with the antitumor efficacy of a PI3K inhibitor ZSTK474 in vitro and in vivo, suggesting that it might be used as a predictive biomarker. In this study, to evaluate biomarker candidates in in vivo tumor samples, we developed an immunohistochemical protein detection/quantification system in conjunction with the tissue microarray technology using a panel of 24 human tumor xenografts (JFCR24). We have clearly demonstrated that expression levels of phosphorylated v-akt murine thymoma viral oncogene homolog (Akt) and mitogen-activated protein kinase (MAPK) determined by this system significantly correlated with those determined by immunoblot analysis. As expected, PTEN status correlated with expression of phosphorylated Akt but not MAPK. Finally, we confirmed that phosphorylated Akt levels determined using this system correlated with the in vivo efficacy of ZSTK474. The present results indicate that the immunohistochemical protein detection/quantification system could be used to quantify expression of biomarker proteins in xenografted tumor tissues as well as in human tumor specimens to predict drug efficacy in future clinical trials.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Immunohistochemistry/methods ; Mice ; Mice, Nude ; Microarray Analysis/methods ; Mitogen-Activated Protein Kinases/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphorylation ; Proteins/immunology ; Proteins/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reproducibility of Results ; Transplantation, Heterologous ; Triazines/pharmacology
    Chemical Substances Biomarkers ; Enzyme Inhibitors ; Proteins ; Triazines ; ZSTK474 ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
    Language English
    Publishing date 2012-08-27
    Publishing country Japan
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
    ZDB-ID 1150271-x
    ISSN 1347-5215 ; 0918-6158
    ISSN (online) 1347-5215
    ISSN 0918-6158
    DOI 10.1248/bpb.b12-00327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1474: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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