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 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.
Erickson-Miller
Connie L
CL
GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. erickc00@gsk.com
Delorme
Evelyne
E
Tian
Shin-Shay
SS
Hopson
Christopher B
CB
Landis
Amy J
AJ
Valoret
Elizabeth I
EI
Sellers
Teresa S
TS
Rosen
Jon
J
Miller
Stephen G
SG
Luengo
Juan I
JI
Duffy
Kevin J
KJ
Jenkins
Julian M
JM
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D002679:Pan troglodytes; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
D018952:Antigens, CD34; D001565:Benzoates; D006834:Hydrazines; D040201:Platelet Membrane Glycoprotein IIb; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D053148:Caspase 3; D053179:Caspase 7; C520809:eltrombopag