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 Blood, 1 July 2004, Vol. 104, No. 1, pp. 58-64.
Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-10-3623.

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HEMATOPOIESIS

Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities

Koji Inagaki, Tomohiro Oda, Yuichi Naka, Hisashi Shinkai, Norio Komatsu, and Hiroyuki Iwamura

From the Japan Tobacco Inc Central Pharmaceutical Research Institute, Osaka, Japan; and the Division of Hematology, Department of Medicine, Jichi Medical School, Tochigi, Japan.

We report in this paper that a novel small molecule, JTZ-132, induced growth and differentiation of megakaryocytic progenitor cells and improved thrombocytopenia in myelosuppressed mice. JTZ-132 stimulated proliferation of UT-7/TPO cells, a cell line highly sensitive to thrombopoietin (TPO), and exhibited full efficacy comparable to TPO with an approximate EC50 (median effective concentration) value of 0.43 µM, whereas little proliferation was observed in a TPO-insensitive cell line, UT-7/EPO, and human carcinoma cell line, HCT116. Signal transduction studies revealed that JTZ-132 induced tyrosine phosphorylation of c-Mpl, Janus kinase-2 (JAK2), and signal transducers and activators of transcription 5 (STAT5) in UT-7/TPO cells as well as TPO. JTZ-132 increased the number of megakaryocyte-specific marker, CD61+ and CD41+, cells in cultures of mouse and human bone marrow cells, respectively, and the colonyforming unit megakaryocytes in mouse bone marrow cells. In vivo experiments in x-ray irradiation– or busulfan injection–induced myelosuppressed mice demonstrated that subcutaneously injected JTZ-132 at 30 mg/kg showed significantly higher platelet number at nadir and accelerated platelet recovery without affecting white blood cell number. These data suggest that JTZ-132 is a novel stimulator of megakaryocytopoiesis and thrombocytopoiesis in vitro and in vivo with TPO mimetic activities and that it is useful for the treatment of thrombocytopenia.


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