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Drug-Target Interaction

Drug

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PubChem ID:3795
Structure:
Synonyms:
"4-[(3′-bromo-4′-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline"
2-Bromo-4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol
4-(3'-bromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
4-[(3′-Bromo-4′-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline
AC1L1GQB
C113888
CHEBI:558489
CHEMBL473773
CID3795
HMS3229G09
IN1289
JAK3 Inhibitor II
MASTPROM
nchembio.2007.59-comp11
SR-02000000171
SR-02000000171-1
WHI P154
WHI-P154
WHIP154
ZINC01488362

Target

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Uniprot ID:PK3C3_HUMAN
Synonyms:
Phosphatidylinositol 3-kinase catalytic subunit type 3
Phosphatidylinositol 3-kinase p100 subunit
Phosphoinositide-3-kinase class 3
PI3-kinase type 3
PI3K type 3
PtdIns-3-kinase type 3
EC-Numbers:2.7.1.137
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
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References:

17353907
Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.. M Marzec; M Kasprzycka; X Liu; M El-Salem; K Halasa; P N Raghunath; R Bucki; P Wlodarski; M A Wasik (2007) Oncogene display abstract
The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as determined by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymatic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies.