Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis.
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.
Yamane
Noriko
N
Discovery Research Laboratories, Shionogi and Company, 1-1, Futaba-cho 3-chome, Toyonaka-shi, Osaka 561-0825, Japan. noriko.yamane@shionogi.co.jp
Takahashi
Koji
K
Tanaka
Yoshikazu
Y
Kato
Kazue
K
Takayama
Masami
M
Ohyabu
Naoki
N
Shiota
Takeshi
T
Takenaka
Hideyuki
H
Yoshida
Yutaka
Y
Hara
Shinichiro
S
Murashi
Takami
T
Nakamura
Etsuo
E
Nishitani
Yoshinori
Y
Ishizaki
Jun
J
Yamane
Shoji
S
Nagata
Kiyoshi
K
Koizumi
Kenzo
K
Yutsudo
Takashi
T
Suzuki
Ryuji
R
Itoh
Tsunetoshi
T
Takemoto
Hiroshi
H
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*
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