Inhibition of PI3K signaling Spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies

J.G. Foster, M.D. Blunt, E. Carter, S.G. Ward

Research output: Contribution to journalArticle

  • 64 Citations

Abstract

The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/ mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractzts for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.
LanguageEnglish
Pages1027-1054
Number of pages28
JournalPharmacological Reviews
Volume64
Issue number4
DOIs
StatusPublished - 1 Oct 2012

Fingerprint

Hematologic Neoplasms
Phosphatidylinositol 3-Kinases
Autoimmune Diseases
Therapeutics
Protein Isoforms
TOR Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
1-Phosphatidylinositol 4-Kinase
Immune System Diseases
Phosphoric Monoester Hydrolases
Pharmaceutical Preparations
Antineoplastic Agents
Lymphoma
Leukocytes
Animal Models
Clinical Trials
Pharmacology
Lipids

Cite this

Inhibition of PI3K signaling Spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. / Foster, J.G.; Blunt, M.D.; Carter, E.; Ward, S.G.

In: Pharmacological Reviews, Vol. 64, No. 4, 01.10.2012, p. 1027-1054.

Research output: Contribution to journalArticle

@article{4bfa6b1f65d6407fb4f9bf2562d583c8,
title = "Inhibition of PI3K signaling Spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies",
abstract = "The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/ mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractzts for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.",
author = "J.G. Foster and M.D. Blunt and E. Carter and S.G. Ward",
year = "2012",
month = "10",
day = "1",
doi = "10.1124/pr.110.004051",
language = "English",
volume = "64",
pages = "1027--1054",
journal = "Pharmacological Reviews",
issn = "0031-6997",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

TY - JOUR

T1 - Inhibition of PI3K signaling Spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies

AU - Foster,J.G.

AU - Blunt,M.D.

AU - Carter,E.

AU - Ward,S.G.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/ mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractzts for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.

AB - The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/ mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractzts for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.

UR - http://www.scopus.com/inward/record.url?scp=84867091296&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1124/pr.110.004051

U2 - 10.1124/pr.110.004051

DO - 10.1124/pr.110.004051

M3 - Article

VL - 64

SP - 1027

EP - 1054

JO - Pharmacological Reviews

T2 - Pharmacological Reviews

JF - Pharmacological Reviews

SN - 0031-6997

IS - 4

ER -