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Drug-Target Interaction

Drug

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PubChem ID:3973
Structure:
Synonyms:
"insolution™ ly 294002"
"ly 294002; 2-(4-morpholino)-8-phenyl-4h-1-benzopyran-4-one"
154447-36-6
1yi3
2-(4-Morpholino)-8-phenyl-4H-1-benzopyran-4-one
2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
2-MORPHOLIN-4-YL-7-PHENYL-4H-CHROMEN-4-ONE
2-morpholin-4-yl-8-phenyl-4H-chromen-4-one
2-morpholin-4-yl-8-phenylchromen-4-one
4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl
4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl-
4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl- (9CI)
8-Phenyl-2-(morpholin-4-yl)-chromen-4-one
AC1L1H4N
AC1Q6CLU
AIDS-223867
AIDS223867
AR-1J3542
BCBcMAP01_000117
Bio1_000332
Bio1_000821
Bio1_001310
Bio2_000442
Bio2_000922
BiomolKI2_000037
BiomolKI_000029
BMK1-D5
BRD-K27305650-001-05-9
BSPBio_001223
C085911
C15195
CBiol_002046
CCG-100633
CHEMBL98350
DB02656
EC-000.2341
H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl- (9CI)
HMS1362M05
HMS1792M05
HMS1990M05
HMS3229G17
HSCI1_000206
IDI1_002197
IN1266
IN1268
InSolution&trade
InSolution™ LY 294002
K00235
KBio2_000563
KBio2_003131
KBio2_005699
KBio3_001005
KBio3_001006
KBioGR_000563
KBioSS_000563
Kinome_3543
Lopac-L-9908
Lopac0_000710
LS-39828
LY 294002
LY 294002; 2-(4-Morpholino)-8-phenyl-4H-1-benzopyran-4-one
LY-294,002
LY-294,002 hydrochloride
LY-294002
LY-924002
LY2
LY294002
LY294002-Supplied by Selleck Chemicals
Lys 294002
NCGC00015622-01
NCGC00015622-02
NCGC00015622-03
NCGC00015622-04
NCGC00015622-05
NCGC00015622-06
NCGC00015622-07
NCGC00025020-01
NCGC00025020-02
NCGC00025020-03
NCGC00025020-04
NCGC00179253-01
nchembio790-comp36
NCI60_034712
NSC697286
S1105_Selleck
Tocris-1130
ZINC00006014

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:
----
----
----

References:

10927021
Suppression of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated aryl hydrocarbon receptor transformation and CYP1A1 induction by the phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1- benzopyran-4-one (LY294002).. M Guo; A Joiakim; J J ReinersJr (2000) Biochemical pharmacology display abstract
Numerous flavonoids are ligands of the aryl hydrocarbon receptor (AHR) and function as AHR antagonists and/or agonists. LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] is a widely used inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), and is structurally related to members of the flavonoid family. Concentrations of LY294002 >/= 10 microM were cytostatic, but not cytotoxic, to cultures of the immortalized human breast epithelial cell line MCF10A-Neo. Treatment of MCF10A-Neo cultures with the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stimulated the transcriptional activation of CYP1A1, as monitored by measurements of steady-state CYP1A1 mRNA. Pretreatment of cultures with >/= 10 microM LY294002 suppressed the TCDD activation of CYP1A1 (IC(50) approximately 10 microM). Electrophoretic mobility shift assays employing rat liver cytosol demonstrated that concentrations of LY294002 /= 10 nM completely suppressed PI 3-kinase activity. Hence, the ability of LY294002 to suppress TCDD-dependent activation of CYP1A1 is unrelated to PI 3-kinase inhibition. Instead, this activity reflects LY294002 functioning as an AHR antagonist. Furthermore, most of the cytostatic activity of LY294002 towards MCF10A-Neo cells is unrelated to the inhibition of PI 3-kinase.
12060646
Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line.. Victoria Smith; Martin G Rowlands; Elaine Barrie; Paul Workman; Lloyd R Kelland (2002) Clinical cancer research : an official journal of the American Association for Cancer Research display abstract
R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials. As acquired drug resistance may limit the efficacy of the drug, a model of acquired resistance has been established in vitro by continuous drug exposure of the human colon cancer cell line KM12. A stably resistant cell line possessing 13-fold resistance to R115777 was generated. The resistant cells showed cross-resistance to another, structurally different farnesyl transferase inhibitor-277, but not to GGTI-298. A lack of cross-resistance was observed to a variety of other agents, which included clinically used drugs, such as doxorubicin, etoposide, cisplatin, and paclitaxel, as well as signal transduction blockers, such as the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor UO126, the phosphatidylinositol 3'-kinase inhibitor LY294002, and the epidermal growth factor receptor tyrosine kinase inhibitor PD153035. Resistance did not appear to be related to differences in drug efflux pumps, such as P-glycoprotein or in drug accumulation. Total levels of farnesyl transferase protein subunits were similar in the parent and resistant cells, but, notably, the enzyme activity was markedly reduced in the resistant cell line compared with the parent cells. This was not because of a mutation in the enzyme or a difference in activation of the alpha-subunit of farnesyl transferase by phosphorylation. Hence, resistance to R115777 was generated; the mechanism of resistance in this model may be associated with the enzyme target of the inhibitor. The results suggest that the development of clinical resistance may occur with farnesyl protein transferase inhibitors.
15475435
Modulation of DNA repair in vitro after treatment with chemotherapeutic agents by the epidermal growth factor receptor inhibitor gefitinib (ZD1839).. Benjamin Friedmann; Martyn Caplin; John A Hartley; Daniel Hochhauser (2004) Clinical cancer research : an official journal of the American Association for Cancer Research display abstract
PURPOSE: The epidermal growth factor receptor (EGFR) is commonly expressed in human tumors and provides a target for therapy. Gefitinib (Iressa, ZD1839) is a quinazoline derivative that inhibits EGFR tyrosine kinase activity. Gefitinib demonstrated anticancer efficacy in vivo, and although experiments in vitro have suggested that inhibition of EGFR modulates the activity of chemotherapeutic agents, the mechanism of this interaction is unclear. We investigated mechanisms for this modulation. EXPERIMENTAL DESIGN: The antiproliferative effect of gefitinib alone or combined with cisplatin, melphalan, and etoposide was determined in a human breast (MCF-7) cancer cell line. Using the alkaline single-cell gel electrophoresis (comet) assay, we investigated kinetics of DNA damage and repair after treatment with the chemotherapeutic drugs combined with gefitinib. To investigate whether the phosphatidylinositol 3'-kinase pathway was contributing to repair-inhibition produced by gefitinib, cells were exposed to chemotherapy in combination with the phosphatidylinositol 3'-kinase inhibitor LY294002. RESULTS: A superadditive (synergistic) increase in growth inhibition for combined treatment with gefitinib was found for cisplatin and etoposide, but not with melphalan. There was delayed repair of DNA strand breaks after treatment with etoposide combined with gefitinib, and repair of DNA interstrand cross-links produced by cisplatin is delayed in combination with gefitinib. Inhibition of cell proliferation and DNA repair was identical in cells treated with LY294002. Immunoprecipitation of cell extracts demonstrated that after exposure to gefitinib, there was an association between EGFR and DNA-PK(CS). CONCLUSION: Gefitinib acts through inhibition of repair of cisplatin and etoposide-induced DNA damage; this effect is mimicked by inhibitors of the phosphatidylinositol 3'-kinase suggesting similar mechanisms of action.