scholarly journals Docking Study to Predict the Efficacy of Phosphatidylinositol 3-Kinase α Inhibitors

2019 ◽  
Vol 7 (2) ◽  
pp. 47-52
Author(s):  
Mahmoud A. Chawsheen ◽  
Hazem A. Al-Bustany
Keyword(s):  
Cancer Progression ◽  
Hydrophobic Interactions ◽  
Docking Study ◽  
Binding Pocket ◽  
Phosphatidylinositol 3 Kinase ◽  
Inhibitory Effects ◽  
Docking Score ◽  
Genes Encoding ◽  
Lipid Kinases ◽  
Phosphatidylinositol 3

The phosphatidylinositol 3-kinase (PI3K) family comprises lipid kinases that cross-link signals between living cells and their surroundings. PI3Ks are classified into several groups and isoforms with specific characteristics and functions. Genes encoding PI3Ks are mutated in several types of cancer, and their isoforms have varying capacity in promoting cell signaling and cancer progression. Many compounds have been introduced as PI3Kα inhibitors, but not all of them have the same inhibitory effects. For successful PI3K-related biomedical experiments, it is vital to select the most specific and potent compounds with the highest inhibitory effects for targeting this kinase. In this study, we investigate 28 well-recognized PI3Kα inhibitors through predicting their specificity and potency using the docking software AutoDock Vina. Our data showed that PF 05212384 had the highest docking score (−9.2 kcal/mol), and 3-methyladenine had the lowest docking score (−4.8 kcal/mol). Our data also showed different types of interactions and bonds formed between the inhibitors and protein residues. In conclusion, PF 05212384 and AZD 6482 compounds are the best candidates for targeting PI3Kα. In addition to hydrophobic interactions in the PI3Kα binding pocket, the formation of hydrogen bonds between these inhibitors and binding pocket residues was confirmed.

scholarly journals Synthesis, Characterization and Docking Study of Novel Pyrimidine Derivatives as Anticancer Agents

2020 ◽  
Vol 20 (5) ◽  
pp. 1163
Author(s):  
Manal Mohamed Talaat El-Saidi ◽  
Ahmed Ali El-Sayed ◽  
Erik Bjerregaard Pedersen ◽  
Mohamed Abdelhamid Tantawy ◽  
Nadia Ragab Mohamed ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Hydrophobic Interactions ◽  
B Cell Lymphoma ◽  
Docking Study ◽  
Receptor Protein ◽  
Binding Modes ◽  
Dependent Protein ◽  
Base Ring

New compounds 5 and 9 using DNA bases e.g. Adenine 1 and Guanine 6 derivatives have been synthesized. The use of simple methods to synthesize compounds 5 and 9 were done using pyrimidine as an alternative DNA base ring. Another design to synthesize new simple pyrimidine rings utilizing thiourea and ethylcyano acetate to afford 6-amino-2-thiouracil was adopted. The reaction of thiouracil 10 with chloro cyano or chloro ester and ketone, resulted in the formation of adduct compounds 18-21, rather than the formation of compound 17. All the synthesized compounds were subjected to docking study, in order to gain insights into their binding modes against cyclin-dependent protein kinase 2 (CDK-2) that is involved heavily in cell cycle regulation and receptor protein B-cell lymphoma 2 (BCL-2) which is involved in cell apoptosis. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses showed that compound 14e was the best docked ligand against both targets, as it displayed the lowest binding energy, critical hydrogen bonds and hydrophobic interactions with the targets.

scholarly journals Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769552 ◽  
Author(s):  
Ebubekir Dirican ◽  
Mustafa Akkiprik
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3

Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%–30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.

scholarly journals Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85.

1993 ◽  
Vol 13 (12) ◽  
pp. 7677-7688 ◽  
Author(s):  
P Hu ◽  
A Mondino ◽  
E Y Skolnik ◽  
J Schlessinger
Keyword(s):  
Cell Cycle Progression ◽  
Phosphatidylinositol 3 Kinase ◽  
Intact Cells ◽  
Src Homology 2 ◽  
Genes Encoding ◽  
Src Homology ◽  
Acid Domain ◽  
Vacuolar Protein ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated as a participant in signaling pathways regulating cell growth by virtue of its activation in response to various mitogenic stimuli. Here we describe the cloning of a novel and ubiquitously expressed human PI 3-kinase. The 4.8-kb cDNA encodes a putative translation product of 1,070 amino acids which is 42% identical to bovine PI 3-kinase and 28% identical to Vps34, a Saccharomyces cerevisiae PI 3-kinase involved in vacuolar protein sorting. Human PI 3-kinase is also similar to Tor2, a yeast protein required for cell cycle progression. Northern (RNA) analysis demonstrated expression of human PI 3-kinase in all tissues and cell lines tested. Protein synthesized from an epitope-tagged cDNA had intrinsic PI 3-kinase activity and associated with the adaptor 85-kDa subunit of PI 3-kinase (p85) in intact cells, as did endogenous human PI 3-kinase. Coprecipitation assays showed that a 187-amino-acid domain between the two src homology 2 domains of p85 mediates interaction with PI 3-kinase in vitro and in intact cells. These results demonstrate the existence of different PI 3-kinase isoforms and define a family of genes encoding distinct PI 3-kinase catalytic subunits that can associate with p85.

scholarly journals Synthesis of Pelorol and Its Analogs and Their Inhibitory Effects on Phosphatidylinositol 3-Kinase

Marine Drugs ◽  
2016 ◽  
Vol 14 (6) ◽  
pp. 118
Author(s):  
Yongjie Luo ◽  
Huixuan Chen ◽  
Jiang Weng ◽  
Gui Lu
Keyword(s):  
Phosphatidylinositol 3 Kinase ◽  
Inhibitory Effects ◽  
Phosphatidylinositol 3

Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression

2004 ◽  
Vol 170 (10) ◽  
pp. 1088-1094 ◽  
Author(s):  
Pierre P. Massion ◽  
Peter M. Taflan ◽  
Yu Shyr ◽  
S. M. Jamshedur Rahman ◽  
Pinar Yildiz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats

2012 ◽  
Vol 61 (6) ◽  
pp. 551-562 ◽  
Author(s):  
Kazuhiko Haruta ◽  
Shigeyuki Mori ◽  
Naoto Tamura ◽  
Asako Sasaki ◽  
Masakazu Nagamine ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phosphatidylinositol 3 Kinase ◽  
Inhibitory Effects ◽  
Adjuvant Induced Arthritis ◽  
Phosphatidylinositol 3

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

2004 ◽  
Vol 32 (3) ◽  
pp. 480-484 ◽  
Author(s):  
C.A. Lindemans ◽  
P.J. Coffer
Keyword(s):  
Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Apoptotic Pathway ◽  
Survival Factors ◽  
Pi3k Activation ◽  
Lipid Kinases ◽  
Intracellular Signal ◽  
Critical Components ◽  
Apoptotic Effects ◽  
Phosphatidylinositol 3

Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.

scholarly journals Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer

2019 ◽  
Vol 20 (14) ◽  
pp. 3383 ◽  
Author(s):  
Jing Jing Liu ◽  
Jung Yoon Ho ◽  
Hye Won Lee ◽  
Min Wha Baik ◽  
Oyoung Kim ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Combined Therapy ◽  
Cyclin B1 ◽  
Pi3k Inhibitor ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Pi3k Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting β-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.

Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85

1993 ◽  
Vol 13 (12) ◽  
pp. 7677-7688
Author(s):  
P Hu ◽  
A Mondino ◽  
E Y Skolnik ◽  
J Schlessinger
Keyword(s):  
Cell Cycle Progression ◽  
Phosphatidylinositol 3 Kinase ◽  
Intact Cells ◽  
Src Homology 2 ◽  
Genes Encoding ◽  
Src Homology ◽  
Acid Domain ◽  
Vacuolar Protein ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated as a participant in signaling pathways regulating cell growth by virtue of its activation in response to various mitogenic stimuli. Here we describe the cloning of a novel and ubiquitously expressed human PI 3-kinase. The 4.8-kb cDNA encodes a putative translation product of 1,070 amino acids which is 42% identical to bovine PI 3-kinase and 28% identical to Vps34, a Saccharomyces cerevisiae PI 3-kinase involved in vacuolar protein sorting. Human PI 3-kinase is also similar to Tor2, a yeast protein required for cell cycle progression. Northern (RNA) analysis demonstrated expression of human PI 3-kinase in all tissues and cell lines tested. Protein synthesized from an epitope-tagged cDNA had intrinsic PI 3-kinase activity and associated with the adaptor 85-kDa subunit of PI 3-kinase (p85) in intact cells, as did endogenous human PI 3-kinase. Coprecipitation assays showed that a 187-amino-acid domain between the two src homology 2 domains of p85 mediates interaction with PI 3-kinase in vitro and in intact cells. These results demonstrate the existence of different PI 3-kinase isoforms and define a family of genes encoding distinct PI 3-kinase catalytic subunits that can associate with p85.

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