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Drug-Target Interaction

Drug

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PubChem ID:4878
Structure:
Synonyms:
"insolution™ pp2"
1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
1-tert-butyl-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
1-tert-butyl-3-(4-chlorophenyl)pyrazolo[3,4-d]pyrimidin-4-amine
11L-313S
172889-27-9
1H-pyrazolo[3,4-d]pyrimidin-4-amine,
1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-
1H-Pyrazolo[3,4-d]pyrimidin-4-amine, 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)- (9CI)
1qpe
4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine
4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine
9-(4-chlorophenyl)-7-tert-butyl-3,5,8-triaza-7-azoniabicyclo[4.3.0]nona-2,4,6,9-tetraen-2-amine
AC1L1J5T
AC1Q3SH9
AG 1879
AG-1879
AG1879
AGL 1879
AKOS005078101
AR-1C5647
Bio2_000399
Bio2_000879
BiomolKI2_000058
BiomolKI_000052
BMK1-F4
BRD-K95785537-001-03-3
BRD-K95785537-001-04-1
BRD-K95785537-001-10-8
BSPBio_001118
C412373
CCG-100656
CHEBI:160597
CHEMBL406845
EC-000.2432
HMS1362H19
HMS1792H19
HMS1990H19
HMS2182N11
IDI1_002154
IN1144
InSolution&trade
InSolution™ PP2
K00048
KBio2_000458
KBio2_003026
KBio2_005594
KBio3_000855
KBio3_000856
KBioGR_000458
KBioSS_000458
Kinome_2000
ksc-8-108
KUC104577N
MLS000326622
MolPort-002-854-321
NCGC00163385-01
NCGC00163385-02
NCGC00163385-03
NCGC00163385-04
Oprea1_738267
PP 2
PP 2 (enzyme inhibitor)
pp2
PP2 cpd
PP2-AG1879
QTL1_000068
SMR000179218
Src family kinase inhibitor PP2
VU0205247-1
ZINC01383151

Target

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Uniprot ID:ICE_DROME
Synonyms:
Caspase
drICE
EC-Numbers:3.4.22.-
Organism:Drosophila melanogaster
Fruit fly
PDB IDs:-

Binding Affinities:

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

References:

15073106
Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells.. Mark S Duxbury; Hiromichi Ito; Michael J Zinner; Stanley W Ashley; Edward E Whang (2004) Clinical cancer research : an official journal of the American Association for Cancer Research display abstract
PURPOSE: We tested the hypotheses that Src tyrosine kinase overactivity represents a chemoresistance mechanism and that Src inhibition may enhance gemcitabine cytotoxicity in pancreatic adenocarcinoma cells. EXPERIMENTAL DESIGN: Pancreatic adenocarcinoma cells PANC1, MiaPaCa2, Capan2, BxPC3, and PANC1(GemRes), a stably gemcitabine-resistant subline of PANC1, were exposed to combinations of gemcitabine and Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). Src expression, phosphorylation (Tyr-416), and activity were analyzed by immunoblotting and in vitro kinase assay. Expression of the M2 subunit of ribonucleotide reductase (RRM2), a putative chemoresistance enzyme, was quantified by Northern and Western blot. Cellular proliferation was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was characterized by YO-PRO-1/propidium iodide staining, fluorometric caspase profiling, and caspase inhibition (Z-Val-Ala-Asp-fluoromethyl ketone). The effects of constitutively active and dominant negative Src were determined. The therapeutic efficacy of PP2 in combination with gemcitabine was tested in nude mice orthotopically xenografted with PANC1(GemRes). RESULTS: Greater gemcitabine resistance was associated with higher Src phosphorylation and activity, both of which were higher in PANC1(GemRes), relative to PANC1; total Src levels were alike. PANC1(GemRes) overexpressed RRM2. PP2 enhanced inherent gemcitabine chemosensitivity and attenuated gemcitabine resistance in PANC1(GemRes). Constitutively active Src increased gemcitabine chemoresistance; dominant negative Src impaired gemcitabine chemoresistance. PP2 augmented gemcitabine-induced caspase-mediated apoptosis, suppressed RRM2 expression, and decreased activity of the RRM2-regulating transcription factor E2F1 in PANC1(GemRes). PP2 and gemcitabine in combination substantially decreased tumor growth and inhibited metastasis in vivo. CONCLUSIONS: Increased Src tyrosine kinase activity represents a potential chemoresistance mechanism and a promising therapeutic target warranting further investigation in gemcitabine-resistant pancreatic adenocarcinoma.