title: Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis.
abstract: We have identified a series of novel non-peptide compounds that activate the thrombopoietin-dependent cell line Ba/F3-huMPL. The compounds stimulated proliferation of Ba/F3-huMPL in the absence of other growth factors, but did not promote proliferation of the thrombopoietin-independent parent cell line Ba/F3. The thrombopoietin-mimetic compounds elicited signal-transduction responses comparable with recombinant human thrombopoietin, such as tyrosine phosphorylation of the thrombopoietin receptor, JAK (Janus kinase) 2, Tyk2 (tyrosine kinase 2), STAT (signal transducer and activator of transcription) 3, STAT5, MAPKs (mitogen-activated protein kinases), PLCgamma (phospholipase Cgamma), Grb2 (growth-factor-receptor-bound protein 2), Shc (Src homology and collagen homology), Vav, Cbl and SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) and increased the number of CD41(+) cells (megakaryocyte lineage) in cultures of human CD34(+) bone-marrow cells (haematopoietic stem cells). These findings suggest that this series of compounds are novel agonists of the human thrombopoietin receptor and are possible lead compounds for the generation of anti-thrombocytopaenia drugs.
authors.affiliation: Discovery Research Laboratories, Shionogi and Company, 1-1, Futaba-cho 3-chome, Toyonaka-shi, Osaka 561-0825, Japan. noriko.yamane@shionogi.co.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamane
authors.forename: Koji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kazue
authors.initials: K
authors.lastname: Kato
authors.forename: Masami
authors.initials: M
authors.lastname: Takayama
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohyabu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiota
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takenaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hara
authors.forename: Takami
authors.initials: T
authors.lastname: Murashi
authors.forename: Etsuo
authors.initials: E
authors.lastname: Nakamura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishitani
authors.forename: Jun
authors.initials: J
authors.lastname: Ishizaki
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamane
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
authors.forename: Kenzo
authors.initials: K
authors.lastname: Koizumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yutsudo
authors.forename: Ryuji
authors.initials: R
authors.lastname: Suzuki
authors.forename: Tsunetoshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D051380:GRB2 Adaptor Protein / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D051966:Phospholipase C gamma / Q000096:biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000096:biosynthesis; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D050799:STAT5 Transcription Factor / Q000096:biosynthesis; D055765:Shc Signaling Adaptor Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D034061:Thrombopoiesis / Q000187:drug effects*; D013926:Thrombopoietin / Q000494:pharmacology*
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; D053628:Receptors, Thrombopoietin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C494087:Stat3 protein, mouse; D013926:Thrombopoietin; D050721:Proto-Oncogene Proteins c-cbl; D011494:Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D051966:Phospholipase C gamma; C067419:CBL protein, human; C493849:Cbl protein, mouse