Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors

2012 ◽  
Vol 22 (6) ◽  
pp. 2230-2234 ◽  
Author(s):  
Hong Lin ◽  
Karl Erhard ◽  
Mary Ann Hardwicke ◽  
Juan I. Luengo ◽  
James F. Mack ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Phosphatidylinositol 3 Kinase ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Phosphatidylinositol 3

scholarly journals Both Src-Dependent and -Independent Mechanisms Mediate Phosphatidylinositol 3-Kinase Regulation of Colony-Stimulating Factor 1-Activated Mitogen-Activated Protein Kinases in Myeloid Progenitors

2000 ◽  
Vol 20 (18) ◽  
pp. 6779-6798 ◽  
Author(s):  
Angel W.-M. Lee ◽  
David J. States
Keyword(s):  
Kinase Inhibitors ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Stimulating Factor ◽  
In Cells ◽  
Phosphatidylinositol 3 ◽  
Myeloid Progenitors

ABSTRACT Colony-stimulating factor 1 (CSF-1) supports the proliferation, survival, and differentiation of bone marrow-derived cells of the monocytic lineage. In the myeloid progenitor 32D cell line expressing CSF-1 receptor (CSF-1R), CSF-1 activation of the extracellular signal-regulated kinase (ERK) pathway is both Ras and phosphatidylinositol 3-kinase (PI3-kinase) dependent. PI3-kinase inhibition did not influence events leading to Ras activation. Using the activity of the PI3-kinase effector, Akt, as readout, studies with dominant-negative and oncogenic Ras failed to place PI3-kinase downstream of Ras. Thus, PI3-kinase appears to act in parallel to Ras. PI3-kinase inhibitors enhanced CSF-1-stimulated A-Raf and c-Raf-1 activities, and dominant-negative A-Raf but not dominant-negative c-Raf-1 reduced CSF-1-provoked ERK activation, suggesting that A-Raf mediates a part of the stimulatory signal from Ras to MEK/ERK, acting in parallel to PI3-kinase. Unexpectedly, a CSF-1R lacking the PI3-kinase binding site (ΔKI) remained capable of activating MEK/ERK in a PI3-kinase-dependent manner. To determine if Src family kinases (SFKs) are involved, we demonstrated that CSF-1 activated Fyn and Lyn in cells expressing wild-type (WT) or ΔKI receptors. Moreover, CSF-1-induced Akt activity in cells expressing ΔKI is SFK dependent since Akt activation was prevented by pharmacological or genetic inhibition of SFK activity. The docking protein Gab2 may link SFK to PI3-kinase. CSF-1 induced Gab2 tyrosyl phosphorylation and association with PI3-kinase in cells expressing WT or ΔKI receptors. However, only in ΔKI cells are these events prevented by PP1. Thus in myeloid progenitors, CSF-1 can activate the PI3-kinase/Akt pathway by at least two mechanisms, one involving direct receptor binding and one involving SFKs.

scholarly journals Alternative signaling pathways from IGF1 or insulin to AKT activation and FOXO1 nuclear efflux in adult skeletal muscle fibers

2020 ◽  
Vol 295 (45) ◽  
pp. 15292-15306
Author(s):  
Sarah J. Russell ◽  
Martin F. Schneider
Keyword(s):  
Muscle Atrophy ◽  
Kinase Inhibitors ◽  
Muscle Fibers ◽  
Therapeutic Interventions ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Promoting Effect ◽  
Adult Skeletal Muscle ◽  
Akt Activation ◽  
Phosphatidylinositol 3

Muscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1–GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1–GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.

Structure−Activity Relationships for a Novel Series of Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors

1997 ◽  
Vol 40 (15) ◽  
pp. 2296-2303 ◽  
Author(s):  
James M. Hamby ◽  
Cleo J. C. Connolly ◽  
Mel C. Schroeder ◽  
R. Thomas Winters ◽  
H. D. Hollis Showalter ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Structure Activity Relationships ◽  
Structure Activity

Synthesis and Structure—Activity Relationships of 5-Heteroatom-Substituted Pyridopyrimidines as Adenosine Kinase Inhibitors.

ChemInform ◽  
2003 ◽  
Vol 34 (31) ◽  
Author(s):  
Gregory A. Gfesser ◽  
Erol K. Bayburt ◽  
Marlon Cowart ◽  
Stanley DiDomenico ◽  
Arthur Gomtsyan ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Adenosine Kinase ◽  
Structure Activity Relationships ◽  
Structure Activity
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