Preclinical Activity of Eltrombopag (SB‐497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist
Eltrombopag is a first‐in‐class, orally bioavailable, small‐molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expr...
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Published in | Stem cells (Dayton, Ohio) Vol. 27; no. 2; pp. 424 - 430 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.02.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Eltrombopag is a first‐in‐class, orally bioavailable, small‐molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen‐activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production. STEM CELLS 2008;27:424–430 |
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Bibliography: | First published online in S Telephone: 610‐917‐4509; Fax: 610‐917‐4181 Disclosure of potential conflicts of interest is found at the end of this article. C Express Author contributions: C.L.E.‐M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; E.D.: conception and design, collection and/or assembly of data, data analysis and interpretation; S.‐S.T.: conception and design, collection and/or assembly of data, data analysis and interpretation; C.B.H.: collection and/or assembly of data, data analysis and interpretation; A.J.L.: collection and/or assembly of data; E.I.V.: collection and/or assembly of data, data analysis and interpretation; T.S.S.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.R.: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; S.G.M.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.I.L.: conception and design, collection and/or assembly of data, data analysis and interpretation; K.J.D.: provision of study material or patients, data analysis and interpretation; J.M.J.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. TEM ELLS November 26, 2008; available online without subscription through the open access option. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 First published online in Stem Cells Express November 26, 2008; available online without subscription through the open access option. Author contributions: C.L.E.-M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; E.D.: conception and design, collection and/or assembly of data, data analysis and interpretation; S.-S.T.: conception and design, collection and/or assembly of data, data analysis and interpretation; C.B.H.: collection and/or assembly of data, data analysis and interpretation; A.J.L.: collection and/or assembly of data; E.I.V.: collection and/or assembly of data, data analysis and interpretation; T.S.S.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.R.: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; S.G.M.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.I.L.: conception and design, collection and/or assembly of data, data analysis and interpretation; K.J.D.: provision of study material or patients, data analysis and interpretation; J.M.J.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. |
ISSN: | 1066-5099 1549-4918 |
DOI: | 10.1634/stemcells.2008-0366 |