Chemically targeting the PI3K family

2007 ◽  
Vol 35 (2) ◽  
pp. 245-249 ◽  
Author(s):  
Z.A. Knight ◽  
K.M. Shokat
Keyword(s):  
Cell Growth ◽  
Recent Progress ◽  
Pi3k Pathway ◽  
Selective Inhibitors ◽  
Growth Metabolism ◽  
Phosphoinositide 3 Kinase ◽  
Widespread Interest

PI3K (phosphoinositide 3-kinase) is a key regulator of cell growth, metabolism and survival. The frequent activation of the PI3K pathway in cancer has stimulated widespread interest in identifying potent and selective inhibitors of PI3K isoforms. The present paper highlights recent progress in identifying such molecules and the challenges that remain for efforts to pharmacologically target the PI3K family.

Structure, function and inhibition of the phosphoinositide 3-kinase p110α enzyme

2014 ◽  
Vol 42 (1) ◽  
pp. 120-124 ◽  
Author(s):  
Jack U. Flanagan ◽  
Peter R. Shepherd
Keyword(s):  
Structure Function ◽  
Present Article ◽  
Recent Progress ◽  
Pi3k Pathway ◽  
Structure And Function ◽  
Selective Inhibitors ◽  
Oncogenic Mutations ◽  
Phosphoinositide 3 Kinase ◽  
And Function

The PI3K (phosphoinositide 3-kinase) p110α isoform is activated by oncogenic mutations in many cancers. This has stimulated intense interest in identifying inhibitors of the PI3K pathway as well as p110α-selective inhibitors, and understanding the mechanisms underlying activation by the oncogenic mutations. In the present article, we review recent progress in the structure and function of the p110α enzyme and two of its most common oncogenic mutations, the development of isoform-selective inhibitors, and p110α pharmacology.

scholarly journals Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases

2017 ◽  
Vol 37 (1) ◽  
Author(s):  
Samuel J. Rodgers ◽  
Daniel T. Ferguson ◽  
Christina A. Mitchell ◽  
Lisa M. Ooms
Keyword(s):  
Cell Growth ◽  
Human Cancer ◽  
Pi3k Pathway ◽  
Inositol Polyphosphate ◽  
Ph Domain ◽  
Akt Activation ◽  
Signalling Molecules ◽  
Akt Isoforms ◽  
Breast And Prostate Cancer ◽  
Phosphoinositide 3 Kinase

Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3 facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)P3 is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns(3,4)P2 and PtdIns3P are also important signalling molecules; PtdIns(3,4)P2 together with PtdIns(3,4,5)P3 are required for maximal AKT activation and PtdIns3P activates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss of Pten, Pipp or Inpp4b expression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)P2-mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)P3 signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes.

scholarly journals Phosphoinositide 3-Kinase-Dependent Inhibition of Dendritic Cell Interleukin-12 Production by Giardia lamblia

2008 ◽  
Vol 77 (2) ◽  
pp. 685-693 ◽  
Author(s):  
Joel Désiré Kamda ◽  
Steven M. Singer
Keyword(s):  
Dendritic Cell ◽  
Giardia Lamblia ◽  
Pi3k Pathway ◽  
Interleukin 12 ◽  
Adaptive Responses ◽  
Necrosis Factor Alpha ◽  
Murine Bone Marrow ◽  
Mechanism Of Inhibition ◽  
Enhanced Secretion ◽  
Phosphoinositide 3 Kinase

ABSTRACT Dendritic cell interactions with pathogenic microbes initiate and direct the development of subsequent adaptive responses. The protozoan pathogen Giardia lamblia infects the mammalian small intestine, leading to nutrient malabsorption and diarrhea but rarely causing inflammation. In order to begin to understand how the innate immune system responds to this parasite and shapes the eventual adaptive response, we examined the interaction between parasites and murine bone marrow-derived dendritic cells (DCs). DCs incubated with live parasites or parasite extracts displayed enhanced levels of CD40. The expression of CD80 and CD86 also increased, but less than was seen with lipopolysaccharide-activated DCs. Small amounts of interleukin-6 (IL-6) and tumor necrosis factor alpha were secreted by these DCs, whereas no IL-10 or IL-12 could be detected. Coincubation of DCs with parasite extracts along with known Toll-like receptor (TLR) ligands resulted in enhanced secretion of IL-10 and reduced secretion of IL-12. The levels of major histocompatibility complex class II, CD80, and CD86 were also reduced compared to DCs stimulated with TLR ligands alone. Finally, studies with an extracellular signal-regulated kinase 1/2 pathway inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and anti-IL-10 receptor antibody revealed that the PI3K pathway is the dominant mechanism of inhibition in DCs incubated with both lipopolysaccharide and Giardia. These data suggest that this parasite actively interferes with host innate immunity, resulting in an immune response able to control the infection but devoid of strong inflammatory signals.

Recent progress in small-molecule inhibitors for critical therapeutic targets of necroptosis

2021 ◽  
Author(s):  
Zhennan Fang ◽  
Huiqiang Wei ◽  
Wenfeng Gou ◽  
Leyuan Chen ◽  
Changfen Bi ◽  
...  
Keyword(s):  
Cell Death ◽  
Small Molecule ◽  
Future Development ◽  
Recent Progress ◽  
Small Molecule Inhibitors ◽  
Cell Necrosis ◽  
Significant Progress ◽  
Regulated Cell Death ◽  
Associated Proteins ◽  
Widespread Interest

Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.

scholarly journals Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

Blood ◽  
2018 ◽  
Vol 132 (25) ◽  
pp. 2670-2683 ◽  
Author(s):  
Eleni Kabrani ◽  
Van Trung Chu ◽  
Evangelia Tasouri ◽  
Thomas Sommermann ◽  
Kevin Baßler ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Transcriptional Activity ◽  
Tumor Development ◽  
Pi3k Pathway ◽  
Forkhead Box ◽  
Nuclear Exclusion ◽  
Pi3k Activation ◽  
Phosphoinositide 3 Kinase ◽  
Human And Mouse

Abstract Forkhead box class O1 (FOXO1) acts as a tumor suppressor in solid tumors. The oncogenic phosphoinositide-3-kinase (PI3K) pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B-cell–derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations, which prevent AKT targeting and lock the transcription factor in the nucleus, are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell–derived lymphomagenesis.

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

2015 ◽  
Vol 58 (18) ◽  
pp. 7381-7399 ◽  
Author(s):  
Kenneth Down ◽  
Augustin Amour ◽  
Ian R. Baldwin ◽  
Anthony W. J. Cooper ◽  
Angela M. Deakin ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Selective Inhibitors ◽  
Phosphoinositide 3 Kinase

scholarly journals The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1

2019 ◽  
Vol 12 (581) ◽  
pp. eaau0615 ◽  
Author(s):  
Samuel J. Carpentier ◽  
Minjian Ni ◽  
Jeffrey M. Duggan ◽  
Richard G. James ◽  
Brad T. Cookson ◽  
...  
Keyword(s):  
B Cell ◽  
Yersinia Pseudotuberculosis ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Caspase 1 ◽  
B Cell Receptor Signaling ◽  
Phosphoinositide 3 Kinase

B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1β release from macrophages. Accordingly, caspase-1–dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro–caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.

Effect of surfactant pluronic F-68 on CHO cell growth, metabolism, production, and glycosylation of human recombinant IFN-γ in mild operating conditions

2010 ◽  
Vol 27 (1) ◽  
pp. 181-190 ◽  
Author(s):  
Marie-Françoise Clincke ◽  
Emmanuel Guedon ◽  
Frances T. Yen ◽  
Virginie Ogier ◽  
Olivier Roitel ◽  
...  
Keyword(s):  
Cell Growth ◽  
Operating Conditions ◽  
Cho Cell ◽  
Ifn Γ ◽  
Growth Metabolism

Dependence on glucose limitation of thepCO2 influences on CHO cell growth, metabolism and IgG production

2007 ◽  
Vol 97 (6) ◽  
pp. 1479-1488 ◽  
Author(s):  
Shinya Takuma ◽  
Chikashi Hirashima ◽  
James M. Piret
Keyword(s):  
Cell Growth ◽  
Cho Cell ◽  
Glucose Limitation ◽  
Growth Metabolism
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