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

Abstract:

: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 EC(50) (median effective concentration) value of 0.43 microM, 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 colony-forming 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.

journal_name

Blood

journal_title

Blood

authors

Inagaki K,Oda T,Naka Y,Shinkai H,Komatsu N,Iwamura H

doi

10.1182/blood-2003-10-3623

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

58-64

issue

1

eissn

0006-4971

issn

1528-0020

pii

2003-10-3623

journal_volume

104

pub_type

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