Abstract
Background: Eltrombopag (formerly SB497115) is a first-in-class, orally active thrombopoietin-receptor (TpoR) agonist that stimulates megakaryocyte proliferation and differentiation. This drug is now under investigation in several conditions characterized by thrombocytopenia. Methods: The scope of this review is to illustrate the results of the preclinical studies that led to the discovery and preclinical development of eltrombopag. Articles were identified by a computer-assisted search of the literature published in English. The bibliographies of all retrieved articles were hand searched for further relevant citations. Results/conclusion: The activity of eltrombopag is dependent on expression of the TpoR but does not compete with endogenous Tpo. In vitro experiments suggest that eltrombopag interacts with TpoR at a distance from the binding site for endogenous Tpo. Thrombopoietin receptor stimulation leads to activation of the Janus kinase 2 and signal transducer and activator of transcription (STAT) 5 pathways, ultimately stimulating proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes and increased platelet production. Measurements in platelets in several species indicated that eltrombopag specifically activates only human and chimpanzee STAT pathways. These findings have provided the rationale for the use of eltrombopag in clinical trials.