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Journal articles on the topic 'PI3K TARGET'

Author: Grafiati

Published: 11 September 2023

Last updated: 31 July 2025

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1

Wang, Bi-Dar, Alyssa Lucero, Siyoung Ha та Reyhaneh Yarmohammadi. "PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer". Cancers 17, № 10 (2025): 1610. https://doi.org/10.3390/cancers17101610.

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Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumo

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Diacovo, Thomas, Dosh Whye, Evgeni Efimenko та ін. "Therapeutic Utility of PI3Kγ Inhibition in Leukemogenesis and Tumor Cell Survival". Blood 120, № 21 (2012): 1492. http://dx.doi.org/10.1182/blood.v120.21.1492.1492.

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Abstract Abstract 1492 Aberrant activation of the PI3K/Akt signaling pathway is a frequent event in cancer including various types of leukemia. Consequently, much emphasis has been placed on developing inhibitors that target this pathway. However, this would require an in depth knowledge of the role that specific class I PI3K isoforms (α, β, γ, δ)play in the pathogenesis of a particular hematological malignancy. For instance, PI3Kδ has been shown to be essential for the growth and survival of tumors derived from B cells such as chronic lymphocytic leukemia (CLL). Such knowledge has lead to dev

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Borsari, Chiara, and Matthias P. Wymann. "Targeting Phosphoinositide 3-Kinase – Five Decades of Chemical Space Exploration." CHIMIA 75, no. 12 (2021): 1037. http://dx.doi.org/10.2533/chimia.2021.1037.

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Phosphoinositide 3-kinase (PI3K) takes a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. The discovery of wortmannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the assembly of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. Genetic mouse models and first PI3K isoform-specific inhibitors pinpointed putative therapeutic applications. The recognition of PI3K as target for cancer therapy drove

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Varkaris, Andreas, Ferran Fece de la Cruz, Elizabeth Martin, et al. "Abstract GS03-10: Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations." Cancer Research 84, no. 9_Supplement (2024): GS03–10—GS03–10. http://dx.doi.org/10.1158/1538-7445.sabcs23-gs03-10.

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Abstract Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3Kα inhibitor, is FDA-approved in combination with fulvestrant. Although prior studies have identified potential resistance mechanisms, such as PTEN loss, clinical acquired resistance to orthosteric PI3Kα inhibitors and the role of next-generation allosteric PI3Kα inhibitors remain poorly understood. Methods: To identify on-target and off-target alterations potentially mediating resistance to PI3Kα inhibitors, we used a targeted next-generation sequencing assay (Guardant360; Gua

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Wen, Hanning, Shuai Mao, Mahamadou Djibo та ін. "Abstract 3001: Highly selective and oral bioavailable PI3Kγ inhibitor for cancer immunotherapy by targeting myeloid-derived suppressor cells in tumor". Cancer Research 85, № 8_Supplement_1 (2025): 3001. https://doi.org/10.1158/1538-7445.am2025-3001.

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Abstract Introduction: Phosphoinositide 3-kinases (PI3Ks) are crucial for cell growth, survival, and metabolism, with dysregulated signaling common in cancer. The PI3K family includes four isoforms—PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ—each with distinct roles, where pan-PI3K inhibition often results in toxicity due to broad isoform expression. Existing various PI3K isoform inhibitors, despite in vitro specificity, often act as pan-inhibitors at high in vivo clinical effective concentrations (1μ M to 5μ M). We developed a highly selective PI3Kγ inhibitor that retains its specificity even at therapeut

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Barberis, Laura, та Emilio Hirsch. "Targeting phosphoinositide 3-kinase γ to fight inflammation and more". Thrombosis and Haemostasis 99, № 02 (2008): 279–85. http://dx.doi.org/10.1160/th07-10-0632.

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SummaryThe family of class I phosphoinositide-3-kinase (PI3K) is composed of four lipid kinases involved at multiple levels in innate and adaptive immune responses. Class I PI3Ks are divided into two subclasses, IA and IB, sharing a similar catalytic core. Whereas class IA PI3Ks are primarily activated by receptor tyrosine kinases, the unique element of class IB PI3K (PI3Kγ) is activated by G protein coupled receptors (GPCRs), like chemokine receptors. PI3Kγ is mainly expressed in leukocytes where it plays a significant role in chemotaxis. Here, we report recent advances in the analysis of the

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Miller, Michelle, Philip Thompson, and Sandra Gabelli. "Structural Determinants of Isoform Selectivity in PI3K Inhibitors." Biomolecules 9, no. 3 (2019): 82. http://dx.doi.org/10.3390/biom9030082.

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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity

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Laurent, Pierre-Alexandre, Cédric Garcia, Marie-Pierre Gratacap та ін. "The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation". Thrombosis and Haemostasis 115, № 06 (2016): 1138–46. http://dx.doi.org/10.1160/th15-08-0661.

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SummaryAntiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies (aPL) associated with increased thrombotic risk and pregnancy morbidity. Although aPL are heterogeneous auto-antibodies, the major pathogenic target is the plasma protein β2-glycoprotein 1. The molecular mechanisms of platelet activation by aPL remain poorly understood. Here, we explored the role of the class IA phosphoinositide 3-kinase (PI3K) α and β isoforms in platelet activation by aPL. Compared to control IgG from healthy individuals, the IgG fraction isolated from

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Mercurio, Laura, Martina Morelli, Claudia Scarponi та ін. "PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis". Cells 10, № 10 (2021): 2636. http://dx.doi.org/10.3390/cells10102636.

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The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also

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Kuracha, Murali R., Venkatesh Govindarajan, Brian W. Loggie, Martin Tobi, and Benita L. McVicker. "Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells." International Journal of Molecular Sciences 24, no. 15 (2023): 12331. http://dx.doi.org/10.3390/ijms241512331.

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The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyr

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Perez-Stable, Carlos, Alicia de las Pozas, Medhi Wangpaichitr, et al. "Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death in Prostate Cancer." Cancers 17, no. 10 (2025): 1643. https://doi.org/10.3390/cancers17101643.

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Background. Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer. Methods/Results. We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/m

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Maffei, Angelo, Giuseppe Lembo, and Daniela Carnevale. "PI3Kinases in Diabetes Mellitus and Its Related Complications." International Journal of Molecular Sciences 19, no. 12 (2018): 4098. http://dx.doi.org/10.3390/ijms19124098.

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Recent studies have shown that phosphoinositide 3-kinases (PI3Ks) have become the target of many pharmacological treatments, both in clinical trials and in clinical practice. PI3Ks play an important role in glucose regulation, and this suggests their possible involvement in the onset of diabetes mellitus. In this review, we gather our knowledge regarding the effects of PI3K isoforms on glucose regulation in several organs and on the most clinically-relevant complications of diabetes mellitus, such as cardiomyopathy, vasculopathy, nephropathy, and neurological disease. For instance, PI3K α has

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Xenou, Lydia, та Evangelia A. Papakonstanti. "p110δ PI3K as a therapeutic target of solid tumours". Clinical Science 134, № 12 (2020): 1377–97. http://dx.doi.org/10.1042/cs20190772.

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Abstract From the time of first characterization of PI3K as a heterodimer made up of a p110 catalytic subunit and a regulatory subunit, a wealth of evidence have placed the class IA PI3Ks at the forefront of drug development for the treatment of various diseases including cancer. The p110α isoform was quickly brought at the centre of attention in the field of cancer research by the discovery of cancer-specific gain-of-function mutations in PIK3CA gene in a range of human solid tumours. In contrast, p110δ PI3K was placed into the spotlight of immunity, inflammation and haematologic malignancies

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Raguž, Luka, Theodora A. Constantin, Lukas Bissegger та ін. "Abstract 1954: Development of highly potent, covalent, and selective inhibitors to target PI3Kα in cancer". Cancer Research 84, № 6_Supplement (2024): 1954. http://dx.doi.org/10.1158/1538-7445.am2024-1954.

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Abstract Aberrant PI3K signaling is linked to various forms of cancer and proliferative disease. Approved clinical therapies targeting overactive PI3K are scarce and often accompanied by severe adverse effects due to lack of PI3K isoform selectivity. We recently reported a proprietary covalent proximity scanning (CoPS) approach to selectively target distant cysteines outside of the ATP-binding pocket in kinases. Using CoPS, we developed isoform specific, irreversible covalent PI3Kα inhibitors (cPI3Kαi) with outstanding target engagement profiles. Here, we report structure-guided scaffold and l

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ML, Choudhary. "A Review on Cancer, Cause of Cancer and Treatment: Role of PIK3 Pathway on Cancer." Bioequivalence & Bioavailability International Journal 7, no. 2 (2023): 1–17. http://dx.doi.org/10.23880/beba-16000208.

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The central function of phosphoinositide 3- kinase (PI3K) activation in tumour cell biology has urged a sizeable trouble to target PI3K and/ or downstream kinases similar as AKT and mammalian target of rapamycin (mTOR) in cancer. still, arising clinical data show limited single- agent exertion of impediments targeting PI3K, AKT or mTOR at permitted boluses. One exception is the response to PI3Kδ impediments in habitual lymphocytic leukaemia, where a combination of cell- natural and- foreign conditioning drive efficacity. Then, we review crucial challenges and openings for the clinical developm

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Chen, Shiyi, Wenkang Huang, Xiaoyu Li, Lijuan Gao, and Yiping Ye. "Identifying Active Compounds and Mechanisms of Citrus changshan-Huyou Y. B. Chang against URTIs-Associated Inflammation by Network Pharmacology in Combination with Molecular Docking." Evidence-Based Complementary and Alternative Medicine 2022 (July 13, 2022): 1–10. http://dx.doi.org/10.1155/2022/2156157.

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Purpose. The ripe fruits of Citrus changshan-huyou, known as Quzhou Fructus Aurantii (QFA), have been commonly used for respiratory diseases. The purpose of this study was to investigate their active compounds and demonstrate their mechanism in the treatment of upper respiratory tract infections (URTIs) through network pharmacology and molecular docking. Methods. The prominent compounds of QFA were acquired from TCMSP database. Their targets were retrieved from SwissTargetPrediction database, and target genes associated with URTIs were collected from DisGeNET and GeneCards databases. The targe

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Hutter, Grit, Yvonne Zimmermann, Anna-Katharina Zoellner, et al. "Combination of PI3K and PDPK1 Inhibitors Is Highly Effective in Mantle Cell Lymphoma." Blood 124, no. 21 (2014): 3123. http://dx.doi.org/10.1182/blood.v124.21.3123.3123.

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Abstract Introduction: Mantle cell lymphoma (MCL), is a distinct lymphoma subtype with an aggressive clinical course and a median survival of 3-5 years. New emerging strategies include especially inhibitors of the PI3K/Akt/mTOR pathway which is constitutively activated in MCL and plays a critical role in tumor growth and survival. In the present study we analysed four different PI3K-Inhibitors (IPI-145, CAL101, A66 and TGX221) targeting different isoforms (PI3Kδ/γ, PI3Kδ, PI3Kα and PI3Kβ) for their effectiveness in MCL. Methods: MCL cell lines (Z-138, Mino-1, Granta-519, Jeko-1, Rec-1, Maver-1

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Kücükdisli, Murat, Hassen Bel-Abed, Davide Cirillo, et al. "Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition." Journal of Medicinal Chemistry 66, no. 20 (2023): 14278–302. https://doi.org/10.5281/zenodo.10683812.

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Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure–activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors ca

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Courtney, Kevin D., Ryan B. Corcoran, and Jeffrey A. Engelman. "The PI3K Pathway As Drug Target in Human Cancer." Journal of Clinical Oncology 28, no. 6 (2010): 1075–83. http://dx.doi.org/10.1200/jco.2009.25.3641.

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The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the

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Brosinsky, Paulin, Julia Bornbaum, Björn Warga та ін. "PI3K as Mediator of Apoptosis and Contractile Dysfunction in TGFβ1-Stimulated Cardiomyocytes". Biology 10, № 7 (2021): 670. http://dx.doi.org/10.3390/biology10070670.

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Background: TGFβ1 is a growth factor that plays a major role in the remodeling process of the heart by inducing cardiomyocyte dysfunction and apoptosis, as well as fibrosis thereby restricting heart function. TGFβ1 mediates its effect via the TGFβ receptor I (ALK5) and the activation of SMAD transcription factors, but TGFβ1 is also known as activator of phosphoinositide-3-kinase (PI3K) via the non-SMAD signaling pathway. The aim of this study was to investigate whether PI3K is also involved in TGFβ1–induced cardiomyocytes apoptosis and contractile dysfunction. Methods and Results: Incubation o

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Mujumdar, Vaidehi, Ritchie Delara, Hailey L. Dryden, et al. "In silico design of novel multitarget small molecule inhibitors to treat PTEN-mutant endometrial carcinoma." Journal of Clinical Oncology 42, no. 16_suppl (2024): e15119-e15119. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e15119.

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e15119 Background: Previously we described triple CDK4/6-CDK9 inhibitor, LCI133 for the treatment of endometrial carcinoma (EC). We used in silico modeling to optimize LCI133’s physicochemical properties to increase PI3K p110α potency/ADME to better target epithelial-derived cancers, resulting in nanomolar potent LCI139. We characterized LCI139’s in vitro potency, target specificity, activity in in vitro EC models, safety in normal cell lines. Methods: LCI139 + analogs were designed using computational chemistry based on X-ray crystal structures of each target protein + validated chemistry usi

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Cao, Biyin, Jingyu Zhu, Man Wang, et al. "A Novel PI3K Inhibitor Identified By a High Throughput Virtual Screen Displays Potent Activity Against Multiple Myeloma." Blood 124, no. 21 (2014): 4722. http://dx.doi.org/10.1182/blood.v124.21.4722.4722.

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Abstract The phosphatidylinositol-3-kinase (PI3K) has been developed as a promising target for the treatment of many cancers, including hematological malignancies, such as lymphoma, leukemia, and multiple myeloma (MM). Recent clinical trials have demonstrated Idelalisib, a specific PI3Kdelta inhibitor, reached a total 57% of response rate in relapsed indolent lymphoma and 72% of overall complete rate in relapsed chronic lymphocytic leukemia. MM remains fatal as a cancer of plasma cells because of lack of efficient drugs. Therefore, we tried to find novel PI3K inhibitors for MM therapy. To this

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Wyatt, Garhett, Rachel Steinmetz, Traci Lyons, and Weston Porter. "Abstract PO5-05-08: LOSS OF SINGLEMINDED 2S RESULTS IN A PI3K SUBUNIT SWITCH WHICH DRIVES THERAPEUTIC RESISTANCE IN ESTROGEN RECEPTOR POSITIVE BREAST CANCER." Cancer Research 84, no. 9_Supplement (2024): PO5–05–08—PO5–05–08. http://dx.doi.org/10.1158/1538-7445.sabcs23-po5-05-08.

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Abstract Estrogen receptor (ER) + breast cancer (BC) comprises over 70% of BC cases and are targeted via ER modulated therapies. Despite this, ER+BC patients can experience recurrence within 20 years and the majority of BC related deaths can be attributed to metastatic ER+BC. These distant metastases are commonly diagnosed as endocrine therapy resistant. Thus, there is an unmet need to identify novel biomarkers for treating ER+ patients with metastases. We have identified a tumor suppressor gene, singleminded 2s (SIM2s), expressed in breast epithelial cells that inhibits epithelial to mesenchy

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Beck, Patrick, Kasen Reed Hutchings, Eileen Xu, et al. "PIK3CB as a potential target to regulate chemosensitivity in glioblastoma." Journal of Clinical Oncology 41, no. 16_suppl (2023): e14051-e14051. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e14051.

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e14051 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy but exhibits universally poor outcomes in part due to chemoresistance. Temozolomide (TMZ) can significantly improve overall survival, but resistance mechanisms limit its consistent efficacy. The phosphoinositide 3 kinase (PI3K) pathway is involved in multiple TMZ resistance mechanisms and is highly druggable; however, pan-inhibition of its four grossly homologous but functionally distinct catalytic subunits (PIK3CA/B/D/G encode p110α/β/δ/γ, respectively) was unsuccessful clinically. Therefore, by

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Meadows, Sarah, Sorensen Rick, Yahiaoui Anella, et al. "Up-Regulation of the PI3K Signaling Pathway Mediates Resistance to Idelalisib." Blood 126, no. 23 (2015): 3707. http://dx.doi.org/10.1182/blood.v126.23.3707.3707.

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Abstract Background: Idelalisib (Zydelig®), a potent and selective PI3Kδ inhibitor, was recently approved for the treatment of relapsed CLL, SLL and FL. PI3Kδ is critical for malignant B-cell proliferation, survival and homing, and inhibition results in a rapid decrease in lymphadenopathy and clinical response (Yang et al., Clin Can Res 2015). Although idelalisib is very potent in mitigating disease, most patients experience incomplete response and ultimately progress. To understand the mechanism of resistance, we screened ABC-DLBCL cell lines for sensitivity to idelalisib and selected TMD8, a

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Molins, Joaquim Bellmunt, Lillian Werner, Marta Guix, et al. "PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?" Journal of Clinical Oncology 30, no. 15_suppl (2012): 4582. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4582.

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4582 Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metasta

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Guenther, Andreas, Renate Burger, Wolfram Klapper, Matthias Staudinger, and Martin Gramatzki. "Selective Inhibition Of The PI3K-Alpha Isoform Blocks Myeloma Cell Growth and Survival." Blood 122, no. 21 (2013): 5364. http://dx.doi.org/10.1182/blood.v122.21.5364.5364.

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Abstract Introduction Both, the phosphoinositide-3kinase (PI3K)/AKT pathway as well as its nutrient-dependent downstream target, the mToR (mammalian target of rapamycin) kinase, are essential for the growth and survival of malignant plasma cells. PI3K exists in four isotypes (α - δ), the role of each of these isotypes in multiple myeloma (MM), however, is not defined. Therefore, we evaluated systematically the in vitroanti-myeloma activity of NVP-BYL719 (Novartis), a newly developed inhibitor highly selective for the PI3K α isoform, and compared it with the activity of other inhibitors targeti

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Jeong, Jae Seok, Jong Seung Kim, So Ri Kim, and Yong Chul Lee. "Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management." International Journal of Molecular Sciences 20, no. 14 (2019): 3525. http://dx.doi.org/10.3390/ijms20143525.

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Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistentl

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Lobo, Vítor, Ashly Rocha, Tarsila G. Castro, and Maria Alice Carvalho. "Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms." Polymers 15, no. 7 (2023): 1703. http://dx.doi.org/10.3390/polym15071703.

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The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years, there has been an increase in the search for selective inhibitors of the four class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. A ligand-based and target-based rational drug design strategy was employed to build a virtual library of 105 new compounds. Through this strategy, the four isoforms were compared regarding their activity pocket availability, a

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Smith, Stephen F., Shannon E. Collins, and Pascale G. Charest. "Ras, PI3K and mTORC2 – three's a crowd?" Journal of Cell Science 133, no. 19 (2020): jcs234930. http://dx.doi.org/10.1242/jcs.234930.

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ABSTRACTThe Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms inc

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Rathinaswamy, Manoj K., Udit Dalwadi, Kaelin D. Fleming та ін. "Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation". Science Advances 7, № 35 (2021): eabj4282. http://dx.doi.org/10.1126/sciadv.abj4282.

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The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activ

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Gong, Grace Q., Jackie D. Kendall, James M. J. Dickson та ін. "Combining properties of different classes of PI3Kα inhibitors to understand the molecular features that confer selectivity". Biochemical Journal 474, № 13 (2017): 2261–76. http://dx.doi.org/10.1042/bcj20161098.

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Phosphoinositide 3-kinases (PI3Ks) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high-selectivity and high-affinity characteristics found in existing compounds. Molecular docking, including the prediction of water-mediated interactions, was used to model interactions bet

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Bheemanaboina, Rammohan R. Y. "Isoform-Selective PI3K Inhibitors for Various Diseases." Current Topics in Medicinal Chemistry 20, no. 12 (2020): 1074–92. http://dx.doi.org/10.2174/1568026620666200106141717.

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Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-sel

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Uche, Uzodinma U., Ann R. Piccirillo, Shunsuke Kataoka, Stephanie J. Grebinoski, Louise M. D’Cruz, and Lawrence P. Kane. "PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt." Journal of Experimental Medicine 215, no. 12 (2018): 3165–79. http://dx.doi.org/10.1084/jem.20172018.

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Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated

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Narayanankutty, Arunaksharan. "PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence." Current Drug Targets 20, no. 12 (2019): 1217–26. http://dx.doi.org/10.2174/1389450120666190618123846.

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Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression e

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Goncalves, Marcus D., and Azeez Farooki. "Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia." Integrative Cancer Therapies 21 (January 2022): 153473542110731. http://dx.doi.org/10.1177/15347354211073163.

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Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a com

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Smith, Greg C., Wee Kiat Ong, Gordon W. Rewcastle, Jackie D. Kendall, Weiping Han, and Peter R. Shepherd. "Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo." Biochemical Journal 442, no. 1 (2012): 161–69. http://dx.doi.org/10.1042/bj20111913.

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In in vitro studies class-I PI3Ks (phosphoinositide 3-kinases), class-II PI3Ks and mTOR (mammalian target of rapamycin) have all been described as having roles in the regulation of glucose metabolism. The relative role each plays in the normal signalling processes regulating glucose metabolism in vivo is less clear. Knockout and knockin mouse models have provided some evidence that the class-I PI3K isoforms p110α, p110β, and to a lesser extent p110γ, are necessary for processes regulating glucose metabolism and appetite. However, in these models the PI3K activity is chronically reduced. Theref

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Kang, Byung Woog, and Ian Chau. "Molecular target: pan-AKT in gastric cancer." ESMO Open 5, no. 5 (2020): e000728. http://dx.doi.org/10.1136/esmoopen-2020-000728.

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The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects,

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Chen, Yingwei, Bao-Can Wang, and Yongtao Xiao. "PI3K: A potential therapeutic target for cancer." Journal of Cellular Physiology 227, no. 7 (2012): 2818–21. http://dx.doi.org/10.1002/jcp.23038.

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Schmitz, Alexa E., Shirsa Udgata, Katherine A. Johnson, and Dustin A. Deming. "The Precision-Guided Use of PI3K Pathway Inhibitors for the Treatment of Solid Malignancies." Biomedicines 13, no. 6 (2025): 1319. https://doi.org/10.3390/biomedicines13061319.

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (MTOR) pathway hyperactivation is seen in a multitude of malignancies. Due to the importance of this pathway in numerous critical cellular functions, preclinical and clinical investigations have aimed to target this pathway as an anti-cancer therapeutic strategy. This has led to the development of PI3K, AKT, and MTOR inhibitors for use in cancer patients, leading to multiple FDA approvals over the past decade. In this review, we outline therapeutic targets in PI3K/AKT/MTOR signaling in solid tumors, the current state of usi

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Jia, Wen-Qing, Xiao-Yan Feng, Ya-Ya Liu та ін. "Identification of Phosphoinositide-3 Kinases Delta and Gamma Dual Inhibitors Based on the p110δ/γ Crystal Structure". Letters in Drug Design & Discovery 17, № 6 (2020): 772–86. http://dx.doi.org/10.2174/1570180816666190730163431.

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Background: Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect a diverse array of biological processes in cells, including proliferation, differentiation, survival, and metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases, which has become a very promising drug target, especially for the treatment of cancer. PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid arthritis compared with pan PI3Ks inhibitors. Methods: With the aim of finding more effective PI3Kδ/γ dual inhibi

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Gao, Mingming, Chao Qi, Zhentian Li та ін. "Abstract 1956: Discovery of a novel and potent mutant-selective inhibitor of PI3Kα". Cancer Research 84, № 6_Supplement (2024): 1956. http://dx.doi.org/10.1158/1538-7445.am2024-1956.

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Abstract Gain-of-function mutations in hotspots of PI3Kα including H1047R, E545K, and E542K are well-recognized oncogenic drivers in human cancers. Prevalence of these mutations is enriched in many human malignancies, particularly in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. PI3Kα inhibition showed clear clinical benefit in treating HR+/HER2− breast cancer and has been approved in combination with fulvestrant. First generation PI3Kα inhibitors such as alpelisib and inavolisib, however, have limited selectivity against wild-type (WT)

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Thillai, Kiruthikah, Debashis Sarker, and Claire Wells. "PAK4 as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC)." Journal of Clinical Oncology 35, no. 15_suppl (2017): e23139-e23139. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23139.

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e23139 Background: PDAC is an aggressive cancer and metastatic spread requires reorganization of the actin cytoskeleton, a process dependent on Rho family GTPases and their interaction with downstream effectors. p21 activated kinases (PAK1-6) are effectors of Rho GTPases Cdc42 and Rac, and play a key role in cell migration and survival. PAK4 can be amplified in PDAC and can reciprocally activate the PI3K pathway. Hepatocyte growth factor (HGF), via c-Met, is an established activator of PAK4 and the PI3K pathway and may promote PDAC invasion. We hypothesized that there is a link between PAK4 an

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Bosch, Ana, Zhiqiang Li, Anna Bergamaschi, et al. "PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer." Science Translational Medicine 7, no. 283 (2015): 283ra51. http://dx.doi.org/10.1126/scitranslmed.aaa4442.

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Activating mutations ofPIK3CAare the most frequent genomic alterations in estrogen receptor (ER)–positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearingPIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing E

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Zhang, Xuewei, Masumi Ishibashi, Kazuyuki Kitatani, et al. "Potential of Tyrosine Kinase Receptor TIE-1 as Novel Therapeutic Target in High-PI3K-Expressing Ovarian Cancer." Cancers 12, no. 6 (2020): 1705. http://dx.doi.org/10.3390/cancers12061705.

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Tyrosine kinase receptor TIE-1 plays a critical role in angiogenesis and blood-vessel stability. In recent years, increased TIE-1 expression has been observed in many types of cancers; however, the biological significance and underlying mechanisms remain unknown. Thus, in the present study, we investigated the tumor biological functions of TIE-1 in ovarian cancer. The treatment of SKOV3 ovarian-cancer cells with siRNA against TIE-1 decreased the expression of key molecules in the PI3K/Akt signaling pathway, such as p110α and phospho-Akt, suggesting that TIE-1 is related to the PI3K/Akt pathway

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Blunt, Matthew D., Matthew J. Carter, Marta Larrayoz, et al. "The Dual PI3K/mTOR Inhibitor PF-04691502 Induces Substantial Apoptosis in Chronic Lymphocytic Leukemia Cells in Vitro and Prolongs Survival in the Eµ-TCL1 Mouse Model." Blood 124, no. 21 (2014): 832. http://dx.doi.org/10.1182/blood.v124.21.832.832.

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Abstract Pharmacological inhibition of specific B cell receptor signalling pathways within chronic lymphocytic leukemia (CLL) cells offers the potential for improved therapeutic options with reduced off target toxicity. Idelalisib, the PI3Kδ selective inhibitor, has been approved for CLL and significantly improved overall survival among patients with relapsed CLL in combination with rituximab compared to rituximab alone. In addition to PI3Kδ however, there are three other Class I PI3K isoforms, PI3Kα, PI3Kβ and PI3Kγ, with PI3Kα known to have a role in CLL survival and chemotaxis. In neutrophi

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Chen, Yu-Chen Enya, Melinda Lea Burgess, Antje Blumenthal, et al. "Activation of Fc Gamma Receptor-Dependent Responses to Therapeutic Antibodies By Nurse like Cells Requires PI3Kdelta." Blood 132, Supplement 1 (2018): 3128. http://dx.doi.org/10.1182/blood-2018-99-109719.

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Abstract There is a continued reliance on antibody therapies for treating chronic lymphocytic leukaemia (CLL). Whilst the inclusion of antibody therapies in many standard treatment regimes results in good outcomes, acquired resistance remains a significant clinical challenge for many CLL patients resulting in insensitivity to the antibody treatment. Thus, understanding the mechanisms driving treatment resistance is likely to lead to therapies to reverse resistance and improve patient outcomes. Earlier studies from our laboratory have shown that resistance to therapeutic antibodies, in CLL, is

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Giulino Roth, Lisa, Herman van Besien, Anna Rodina, et al. "Targeting the Hsp90 Oncoproteome in Burkitt Lymphoma." Blood 126, no. 23 (2015): 592. http://dx.doi.org/10.1182/blood.v126.23.592.592.

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Abstract Introduction: Novel therapies are urgently needed in pediatric Burkitt lymphoma (pBL) where the survival for relapsed disease is less than 20%. Heat shock protein 90 (Hsp90) is molecular chaperone that protects proteins from proteolytic degradation including oncogenic signaling complexes. The clinical development of broad-spectrum Hsp90 inhibitors has previously been limited by suboptimal target inhibition and off-target toxicities. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets tumor enriched (te-Hsp90), the functionally distinct pool of Hsp90 present in tumo

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Leiphrakpam, Premila, and Chandrakanth Are. "PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment." International Journal of Molecular Sciences 25, no. 6 (2024): 3178. http://dx.doi.org/10.3390/ijms25063178.

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In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pa

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Rezende, Denise C., Lorena Zaida Pacheco, Luis Arthur F. Pelloso, et al. "PI3K/AKT Pathway as a Potential Therapeutic Target In Myelodysplastic Syndrome." Blood 116, no. 21 (2010): 1871. http://dx.doi.org/10.1182/blood.v116.21.1871.1871.

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Abstract Abstract 1871 Introduction: PI3K/AKT pathway is involved in cell growth, proliferation and apoptosis. A key downstream effector is the phosphorylated serine-threonine Akt (p-AKT). Constitutive activation of PI3K/AKT has been observed in solid tumours and leukemic cells. Inhibition of PI3K/AKT activity, results in apoptosis in cell lines (CL) after treatment with different compounds, e.g. deguelin, a natural product from the leguminous Mundulea sericea, with antitumour effects. Aims: To evaluate PI3K/AKT activation in MDS patients and its therapeutic potential in MDS. Methods: PI3K/AKT

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