Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

Akinleye, Akintunde; Avvaru, Parthu; Furqan, Muhammad; Song, Yongping; Liu, Delong

doi:10.1186/1756-8722-6-88

Cited by 215 publications

(223 citation statements)

References 194 publications

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“…Class I PI3Ks are heterodimeric kinases composed of a catalytic subunit (PIK3CA, PIK3CB, PIK3CD, or PIK3CG) and a regulatory subunit, and they are further subdivided to class IA (with PIK3CA, PIK3CB, or PIK3CD as the catalytic subunit) and class IB (with PIK3CG as the catalytic subunit). 24,25 Class I PI3Ks can phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P 2 in vitro, but they may preferentially use PtdIns(4,5)P 2 to produce PtdIns(3,4,5)P 3 in vivo. 24 Class II PI3Ks are monomeric kinases which have 3 isoforms (PIK3C2A, PIK3C2B and PIK3C2G), and they prefer PtdIns and PtdIns4P as substrates to produce PtdIns3P and PtdIns(4,5)P 2 .…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

“…24,25 Class I PI3Ks can phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P 2 in vitro, but they may preferentially use PtdIns(4,5)P 2 to produce PtdIns(3,4,5)P 3 in vivo. 24 Class II PI3Ks are monomeric kinases which have 3 isoforms (PIK3C2A, PIK3C2B and PIK3C2G), and they prefer PtdIns and PtdIns4P as substrates to produce PtdIns3P and PtdIns(4,5)P 2 . 26 Both class I PI3K and class II PI3K are downstream effectors of receptor tyrosine kinases and G-protein-coupled receptors.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

“…26 Both class I PI3K and class II PI3K are downstream effectors of receptor tyrosine kinases and G-protein-coupled receptors. 24 Note that both class I and II enzymes can function as either phosphatidylinositol 3-kinases (phosphorylating the 3 0 hydroxyl of phosphatidylinositol) or phosphoinositide 3-kinases (i.e., adding an additional phosphate to a phosphoinositide) in vitro, but are referred to as PI3Ks for simplicity. Class III PtdIns3K forms large multi-subunit complexes with PIK3C3 as the catalytic subunit and PIK3R4 as the regulatory subunit, and their composition diversifies in different biological context.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

“…Class III PtdIns3K generates PtdIns3P, and functions as the most pivotal positive regulator of autophagy. 24,27 MTOR (mechanistic target of rapamycin), ATM serine/threonine kinase (ATM), ATR serine/threonine kinase (ATR), and PRKDC (protein kinase, DNA-activated, catalytic polypeptide) constitute the PI3K-related kinase family, sometimes referred to as class IV PI3K, based on their sequence homology with other PI3Ks. 28,29 The mechanistic role of MTOR in autophagy regulation will be reviewed in details below.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

“…The fact that aberrant signaling activity of PtdIns3Ks and PI3Ks is correlated with various pathological conditions and mutations in these enzymes is frequently observed in cancer makes these lipid kinases one of the most sought-after drug targets. 24,172 Based on their target selectivity, the available PtdIns3K and PI3K inhibitors can be classified as pan-PI3K inhibitors, dual PI3K-MTOR inhibitors and class or isoformselective inhibitors, as summarized in Table 3. 24,26,[173][174][175] Pan-PI3K inhibitors have potent inhibitory effect on all class I PI3Ks, but their off-target effects on other PI3K-related kinases such as MTOR confound their application and therefore display unfavorable side effects in clinical trials.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Incidence of Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors as Adjuvant Therapy in Patients With Cancer

et al. 2022

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ImportanceThe phosphoinositide 3-kinase (PI3K) pathway is among the most frequently activated pathways in human cancers. As the use of PI3K inhibitors for cancer treatment grows, there is increasing need for understanding the cutaneous effects associated with these therapies.ObjectiveTo systematically review the published literature reporting incidence of cutaneous adverse events with PI3K inhibitors and to provide pooled incidence estimates using meta-analysis.Data SourcesThis systematic review and meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The literature search concerned entries through September 2021 in the following sources: PubMed, Cochrane registry, ClinicalTrials.gov, and evidence from the NHS UK and Trip medical database. To analyze PI3K inhibitors’ cutaneous adverse events incidence, only randomized clinical trials (RCTs) were considered. The search strategy used the following keywords: (prevalence OR incidence OR epidemiology) and (phosphoinositide 3 kinase inhibitors OR PI3K inhibitors). No language restriction was applied. Analysis was conducted on July 1, 2022.Study SelectionStudies included phase 2 and phase 3 RCTs that reported incidence of cutaneous adverse events associated with use of PI3K inhibitors.Data Extraction and MeasuresData extracted included sex, medication name and class, sample size, rash incidence, and grade. The bias risk was assessed by the Cochrane tool for risk of bias assessment in RCTs.Main Outcomes and MeasuresThe primary outcome was incidence of PI3K inhibitor cutaneous adverse events (with 95% CIs) among the overall population and among subgroups. Between-study heterogeneity was assessed using the I2 statistic.ResultsThe analysis found the incidence of PI3K inhibitor cutaneous events of any grade to be 29.30% in the intervention group, translating to a pooled odds ratio (OR) for incidence of cutaneous adverse events of any grades of 2.55 (95% CI, 1.74-3.75). Incidence of severe grade (grade ≥3) of rash in the intervention group was estimated to be 6.95%, yielding a pooled Peto OR of 4.64 (95% CI, 2.70-7.97). Subgroup analyses revealed that the incidence of severe cutaneous adverse events (grade ≥3) was higher with the use of Pan-class-1 PI3K inhibitors (OR, 6.67; 95% CI, 4.28-10.38) than isoform-selective PI3K inhibitors (OR, 6.37; 95% CI, 3.25-12.48).Conclusions and RelevanceThis systematic review and meta-analysis identified an overall incidence of PI3K inhibitor cutaneous adverse events of any grade to be 29.30% with a pooled OR of 2.55; (95% CI, 1.74-3.75). These findings clarify the risk of cutaneous adverse events associated with this important class of anticancer therapies.

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p110α and p110β isoforms of PI3K signaling: are they two sides of the same coin?

Paramjeet

Dar

2016

FEBS Letters

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Edited by Lukas Alfons HuberClass-1 phosphatidylinositol-3-kinases (PI3Ks) are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes. p110a and p110b are the two most studied isoforms of the class-1A PI3K signaling pathway. Although these two isoforms are ubiquitously expressed and play multiple redundant roles, they also have distinct functions within the cell. More recently, p110a and p110b isoforms have been shown to translocate into the nucleus and play a role in DNA replication and repair, and in cell cycle progression. In the following Review article, we discuss the overlapping and unique roles of p110a and p110b isoforms with a particular focus on their structure, expression analysis, subcellular localization, and signaling contributions in various cell types and model organisms.

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Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

Cited by 215 publications

References 194 publications

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Incidence of Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors as Adjuvant Therapy in Patients With Cancer

p110α and p110β isoforms of PI3K signaling: are they two sides of the same coin?

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