Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis.
High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.
Duffy
K J
KJ
GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Kevin.J.Duffy@gsk.com
Darcy
M G
MG
Delorme
E
E
Dillon
S B
SB
Eppley
D F
DF
Erickson-Miller
C
C
Giampa
L
L
Hopson
C B
CB
Huang
Y
Y
Keenan
R M
RM
Lamb
P
P
Leong
L
L
Liu
N
N
Miller
S G
SG
Price
A T
AT
Rosen
J
J
Shah
R
R
Shaw
T N
TN
Smith
H
H
Stark
K C
KC
Tian
S S
SS
Tyree
C
C
Wiggall
K J
KJ
Zhang
L
L
Luengo
J I
JI
D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D017930:Genes, Reporter; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008533:Megakaryocytes / Q000187:drug effects*; D051379:Mice; D018716:Molecular Mimicry; D008970:Molecular Weight; D009282:Naphthalenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009363:Neoplasm Proteins; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013329:Structure-Activity Relationship; D013926:Thrombopoietin / Q000737:chemistry* / Q000378:metabolism
D001391:Azo Compounds; D006834:Hydrazines; D009282:Naphthalenesulfonates; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; D008156:Luciferases; D010770:Phosphotransferases