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Drug-Target Interaction

Drug

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PubChem ID:6918454
Structure:
Synonyms:
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
2-[(2-CHLORO-4-IODOPHENYL)AMINO]-N-(CYCLOPROPYLMETHOXY)-3,4-DIFLUOROBENZAM
212631-79-3
AC1OCFGE
AG-E-55891
C120227
CHEBI:269054
CHEMBL105442
CI 1040
CI-1040
CI-1040-Supplied by Selleck Chemicals
EC-000.2331
PD 184352
PD-18435
PD-184352
PD184352
PD184352, CI1040
S1020_Selleck
ZINC01489691

Target

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Uniprot ID:MK03_HUMAN
Synonyms:
ERK-1
ERT2
Extracellular signal-regulated kinase 1
Insulin-stimulated MAP2 kinase
MAP kinase 1
MAPK 1
Microtubule-associated protein 2 kinase
Mitogen-activated protein kinase 3
p44-ERK1
p44-MAPK
EC-Numbers:2.7.11.24
Organism:Homo sapiens
Human
PDB IDs:2ZOQ
Structure:
2ZOQ

Binding Affinities:

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

References:

12963734
Central role of Fas-associated death domain protein in apoptosis induction by the mitogen-activated protein kinase kinase inhibitor CI-1040 (PD184352) in acute lymphocytic leukemia cells in vitro.. Xue Wei Meng; Joya Chandra; David Loegering; Keri Van Becelaere; Timothy J Kottke; Steven D Gore; Judith E Karp; Judy Sebolt-Leopold; Scott H Kaufmann (2003) The Journal of biological chemistry display abstract
Because the MAPK pathway plays important roles in cell proliferation and inhibition of apoptosis, this pathway has emerged as a potential therapeutic target for solid tumors and leukemia. At the present time there is little information about activation of this pathway and the consequences of its inhibition in acute lymphocytic leukemia cells (ALL). In the present study, constitutive MAPK pathway activation, as evidenced by phosphorylation of ERK1 and ERK2, was observed in 8 of 8 human lymphoid cell lines and 33% (8:24) of pretreatment ALL bone marrows. Inhibition of this pathway by the MEK inhibitors CI-1040 and PD098059 induced apoptosis through a unique pathway involving dephosphorylation and aggregation of Fas-associated death domain protein followed by death receptor-independent caspase-8 activation. Jurkat cell variants lacking Fas-associated death domain protein or procaspase-8 were resistant to CI-1040-induced apoptosis, as were Jurkat or Molt3 cells treated with the O-methyl ester of the caspase-8 inhibitor N-(Nalpha-benzyloxycarbonylisoleucylglutamyl) aspartate fluoromethyl ketone. In contrast, CI-1040-induced apoptosis was unaffected by blocking anti-Fas antibody, soluble tumor necrosis factor-alpha-related apoptosis-inducing ligand decoy receptor, or transfection with cDNA encoding the anti-apoptotic Bcl-2 family member Mcl-1 or dominant negative caspase-9. Collectively, these results identify the MAPK pathway as a potential therapeutic target in ALL and delineate a mechanism by which MEK inhibition triggers apoptosis in ALL cells.