title: Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis.
abstract: 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.
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Kevin.J.Duffy@gsk.com
authors.forename: K J
authors.initials: KJ
authors.lastname: Duffy
authors.forename: M G
authors.initials: MG
authors.lastname: Darcy
authors.forename: E
authors.initials: E
authors.lastname: Delorme
authors.forename: S B
authors.initials: SB
authors.lastname: Dillon
authors.forename: D F
authors.initials: DF
authors.lastname: Eppley
authors.forename: C
authors.initials: C
authors.lastname: Erickson-Miller
authors.forename: L
authors.initials: L
authors.lastname: Giampa
authors.forename: C B
authors.initials: CB
authors.lastname: Hopson
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: R M
authors.initials: RM
authors.lastname: Keenan
authors.forename: P
authors.initials: P
authors.lastname: Lamb
authors.forename: L
authors.initials: L
authors.lastname: Leong
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.forename: S G
authors.initials: SG
authors.lastname: Miller
authors.forename: A T
authors.initials: AT
authors.lastname: Price
authors.forename: J
authors.initials: J
authors.lastname: Rosen
authors.forename: R
authors.initials: R
authors.lastname: Shah
authors.forename: T N
authors.initials: TN
authors.lastname: Shaw
authors.forename: H
authors.initials: H
authors.lastname: Smith
authors.forename: K C
authors.initials: KC
authors.lastname: Stark
authors.forename: S S
authors.initials: SS
authors.lastname: Tian
authors.forename: C
authors.initials: C
authors.lastname: Tyree
authors.forename: K J
authors.initials: KJ
authors.lastname: Wiggall
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: J I
authors.initials: JI
authors.lastname: Luengo
mesh_terms: 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
chemical_list: 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