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), PLCγ (phospholipase Cγ), 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.
Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis
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Noriko Yamane, Koji Takahashi, Yoshikazu Tanaka, Kazue Kato, Masami Takayama, Naoki Ohyabu, Takeshi Shiota, Hideyuki Takenaka, Yutaka Yoshida, Shinichiro Hara, Takami Murashi, Etsuo Nakamura, Yoshinori Nishitani, Jun Ishizaki, Shoji Yamane, Kiyoshi Nagata, Kenzo Koizumi, Takashi Yutsudo, Ryuji Suzuki, Tsunetoshi Itoh, Hiroshi Takemoto; Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis. Biosci Rep 1 October 2008; 28 (5): 275–285. doi: https://doi.org/10.1042/BSR20080086
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