A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate

Falasca, Marco; Chiozzotto, Daniela; Godage, H. Yasmin; Mazzoletti, Marco; Riley, Andrew M.; Previdi, Sara; Potter, Barry V. L.; Broggini, Massimo; Maffucci, Tania

doi:10.1038/sj.bjc.6605408

Cited by 53 publications

(78 citation statements)

References 50 publications

(70 reference statements)

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“…In contrast, a number of reports indicate that higher-order inositol phosphates antagonize proliferation and tumorigenesis and promote apoptosis (24)(25)(26)(27)(28)(29). Moreover, several studies indicate that higher inositol phosphates specifically decrease Akt activity (26,27,(30)(31)(32). The differential regulation of PIP 3 and inositol phosphate production by IPMK may provide a process enabling cells to switch between Akt activation and inhibition, with corresponding influences upon cellular proliferation and survival (Fig.…”

Section: Resultsmentioning

confidence: 88%

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Maag

Maxwell

Hardesty

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

141

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The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP 3 as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP 3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.signal transduction | cancer A large family of inositol phosphates serves multiple functions, with inositol 1,4,5-trisphosphate (IP 3 ) being well known as a second messenger releasing intracellular calcium (1). Inositol diphosphates, incorporating an energetic pyrophosphate bond, display numerous physiological roles, including pyrophosphorylation of a variety of protein targets (2-4). These inositol pyrophosphates are synthesized by a family of IP 6 kinase enzymes (5). Recently, novel isomers of inositol pyrophosphates have been described that are synthesized by a distinct inositol phosphate kinase enzyme designated Vip1 (6, 7).Inositol polyphosphate multikinase (IPMK) is a member of the IP 6 kinase family of enzymes but is not primarily associated with the formation of inositol pyrophosphates. Instead it generates several inositol phosphates, converting IP 3 to IP 4 and IP 4 to IP 5 , with its primary physiologic role in this pathway being to form the bulk of IP 5 in cells (5,(8)(9)(10)(11). IPMK also possesses phosphatidylinositol 3-kinase (PI3K) activity in vitro (12), specifically phosphorylating phosphatidylinositol(4,5)-bisphosphate (PIP 2 ) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), a second messenger known to promote cellular growth, proliferation, survival, and migration (13). The physiologic role of this activity has not heretofore been established. The principal PI3K activity in cells has been attributed to a family of enzymes identified by Cantley and associates (reviewed in ref. 14), whose catalytic subunits are designated p110. PIP 3 generated by p110 in response to extracellular stimuli, such as growth factors, is a principal stimulus of the Akt/mammalian target of rapamycin (mTOR) signaling pathway, which in turn regulates protein synthesis and plays a role in some cancers (15)(16)(17).We wondered whether the PI3K activity of IPMK contributes to the generation of PIP 3 under physiologic conditions to influence Akt signaling and cell growth. There is good reason to assume that IPMK is ...

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Section: Resultsmentioning

confidence: 88%

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Maag

Maxwell

Hardesty

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

141

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“…Similarly to PtdIns(3,4,5)P 3 in the plasma membrane, InsP5 recruits and binds to PH-domains of different effector molecules such as Akt and prevents their activation by blocking translocation to the plasma membrane [301,302]. Recently, an improved version of InsP5 was synthesised by addition of a benzyl group to InsP5 [305]. 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-OBn-InsP5) not only blocked Akt translocation to the membrane, but also selectively inhibited PDK-1-dependent phosphorylation of Akt.…”

Section: Pi3k Inhibitors In Cancer Treatmentmentioning

confidence: 99%

“…Akt, PDK1) Preclinical Cancer [305] Information about clinical trials status was retrieved from [306].…”

Section: Pi3k Inhibitors In Cancer Treatmentmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase Isoforms as Novel Drug Targets

Błajecka¹,

Borgström²,

Arcaro

2011

CDT

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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.

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“…Mice embryos lacking PDK1 died at embryonic day 9.5, displaying multiple abnormalities, including lack of somites, forebrain and neural crest derived tissue [20]. Furthermore, The antiapoptotic effects of PDK1 have been reported in non-neuronal cells [21,22] and inhibitory activity of PDK1 was shown to inhibit tumor cell growth and to promote apoptosis [23,24]. However, the biological significance of PDK1 and its activation in CNS injury is largely unknown.…”

Section: Introductionmentioning

confidence: 96%

Increase in phosphorylation of PDK1 and cell survival after acute spinal cord injury

Zhong

Huang

Cao

et al. 2012

Journal of the Neurological Sciences

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A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate

Cited by 53 publications

References 50 publications

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Phosphatidylinositol 3-Kinase Isoforms as Novel Drug Targets

Increase in phosphorylation of PDK1 and cell survival after acute spinal cord injury

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