A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).

Vlahos, Chris J.; Matter, William F.; Hui, Kwan Y.; Brown, Raymond F.

doi:10.1016/s0021-9258(17)37680-9

Cited by 2,941 publications

(340 citation statements)

References 55 publications

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“…Both the rank order and, more important, the IC 50 values are in concordance with other studies. 9,13,[28][29][30][31] Notably, the rank order of the inhibitors in these experiments was the same, with a few minor exceptions, regardless of the substrate or detection format. The covalent inhibitor wortmannin 32 was the most potent PI3Kα inhibitor in the series with IC 50 values of 4 nM and 2 nM observed using the C16 substrate with the TR-FRET and FP assay, respectively, and somewhat higher values of 35 nM and 6 nM observed with the C8 substrate.…”

Section: Inhibitor Profiles For Pi3 Kinase Activitymentioning

confidence: 96%

See 1 more Smart Citation

Evaluating PI3 Kinase Isoforms Using Transcreener™ ADP Assays

Klink

Kleman-Leyer²,

Kopp³

et al. 2008

SLAS Discovery

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Development of drugs targeting lipid kinases has been delayed by the lack of robust screening assays. Methods are needed that can accommodate the presentation of different acceptor substrates in the optimal lipid environment. The Transcreener ADP Assay relies on homogeneous immunodetection of adenosine diphosphate (ADP), using either fluorescence polarization (FP) or time-resolved fluorescence resonance energy transfer (TR-FRET) as a signal output. Detection of ADP--the invariant product of all kinase reactions--provides complete flexibility for varying lipid substrate parameters. The authors used this assay to optimize dispersal methods for C8 and C16 phosphatidylinositol 4,5 bisphosphate substrates and to assess the effects of chain length on the activity and inhibition of phosphoinositide-3-kinase (PI3K) isoforms. The nonphysiological C8 substrate supported the highest activity. Known inhibitors were profiled using both the FP- and TR-FRET-based assays, and there was excellent concordance (r(2)=0.93) in the IC(50) values. The overall rank order of inhibitors was the same using the C8 and C16 substrates, except for minor deviations. Adenosine triphosphate (ATP) hydrolysis in the absence of substrate was detected with the PI3Kalpha isoform, and inhibitors affected PI3Kalpha intrinsic ATP hydrolysis activity similarly to lipid phosphorylation.

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Section: Inhibitor Profiles For Pi3 Kinase Activitymentioning

confidence: 96%

“…For comparison, literature IC 50 values with PI3Kα range from 1 to 5 nM for wortmannin and from 1.4 to 3.8 μM for querectin. 8,13,28,29,[32][33][34] Literature values were determined using various assay conditions.…”

Section: Inhibitor Profiles For Pi3 Kinase Activitymentioning

confidence: 99%

Evaluating PI3 Kinase Isoforms Using Transcreener™ ADP Assays

Klink

Kleman-Leyer²,

Kopp³

et al. 2008

SLAS Discovery

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“…These molecules have cytostatic effects with G1 phase arrest in vitro and hallmark anti-cancer effects in vivo [Smith et al, 2009]. The first PI3K inhibitors (LY294002 and wortmannin) did not report selectivity for specific PI3K isoforms and had toxicity in preclinical studies [Powis et al, 1994;Vlahos et al, 1994]. However, PX-866 (C 29 H 35 NO 8 ) is a novel oral agent, pan-isoform inhibitor of PI3K has benefit of target inhibition [Wipf et al, 2004].…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Targeting PI3K/AKT Pathway in Treatment of Colorectal Cancer: Rational and Progress

Bahrami

Amerizadeh

Shahidsales

et al. 2017

J of Cellular Biochemistry

165

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PI3K/AKT/mTOR signaling pathway is one of the key dysregulated pathways in different tumor types, including colorectal cancer (CRC). Activation of this pathway is shown to be related with cellular transformation, tumor progression, cell survival, and drug resistance. There is growing body of data evaluating the value of PI3K/AKT/mTOR inhibitors in CRC (e.g., BEZ235, NVP-BEZ235, OSI-027, everolimus, MK-2206, KRX-0401, BYL719, and BKM120). This report summarizes the current knowledge about PI3K/AKT pathway and its cross talk with ERK/MAPK and mTOR pathways with particular emphasis on the value of targeting this pathway as a potential therapeutic target in treatment of colorectal cancer. J. Cell. Biochem. 119: 2460-2469, 2018. © 2017 Wiley Periodicals, Inc.

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“…LY294002 is a slightly more stable compound and its effects on PI3K are reversible. However, the future of this drug was limited to pathway analysis over clinical development due to constraints with its pharmacological properties [48,51]. Other inhibitors that targeted multiple PI3K proteins were developed that share similar structures to wortmannin and LY294002, including SF1126 and PX-866 [49,52].…”

Section: Pharmacological Targeting Of the Pi3k Pathwaymentioning

confidence: 99%

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Wright

Vasilevski

Serra

et al. 2021

Cancers

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The phosphatidylinositol-3-kinase (PI3K) pathway plays a central role in the regulation of several signalling cascades which regulate biological processes such as cellular growth, survival, proliferation, motility and angiogenesis. The hyperactivation of this pathway is linked to tumour progression and is one of the most common events in human cancers. Additionally, aberrant activation of the PI3K pathway has been demonstrated to limit the effectiveness of a number of anti-tumour agents paving the way for the development and implementation of PI3K inhibitors in the clinic. However, the overall effectiveness of these compounds has been greatly limited by inadequate target engagement due to reactivation of the pathway by compensatory mechanisms. Herein, we review the common adaptive responses that lead to reactivation of the PI3K pathway, therapy resistance and potential strategies to overcome these mechanisms of resistance. Furthermore, we highlight the potential role in changes in cellular plasticity and PI3K inhibitor resistance.

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A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).

Cited by 2,941 publications

References 55 publications

Evaluating PI3 Kinase Isoforms Using Transcreener™ ADP Assays

Evaluating PI3 Kinase Isoforms Using Transcreener™ ADP Assays

Therapeutic Potential of Targeting PI3K/AKT Pathway in Treatment of Colorectal Cancer: Rational and Progress

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

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