Abstract
Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small‐molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR‐expressing cells, including 32D‐MPL and human hematopoietic stem cells, with low nanomolar EC 50 values through stimulation of STAT, PI3K and ERK signalling pathways. Notably, hetrombopag effectively up‐regulated G1‐phase–related proteins, including p‐RB, Cyclin D1 and CDK4/6, normalized progression of the cell cycle, and prevented apoptosis by modulating BCL‐XL/BAK expression in 32D‐MPL cells. Moreover, hetrombopag and TPO acted additively in stimulating TPOR‐dependent signalling, promoting cell viability, and preventing apoptosis. Orally administered hetrombopag specifically promoted the viability and growth of 32D‐MPL cells in hollow fibres implanted into nude mice with much higher potency than that of the well‐known TPOR agonist, eltrombopag, in association with activation of TPOR‐dependent signal transduction in vivo. Taken together, our findings indicate that, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small‐molecule TPOR agonist for patients with thrombocytopenia.
Highlights
Thrombocytopenia, characterized by abnormally low platelet counts in circulating blood, is caused by decreased platelet production and/ or accelerated platelet destruction
Thrombopoietin (TPO), a hematopoietic cytokine that is critically involved in regulating megakaryopoiesis,[5,6] exerts its biological function through activation of the thrombopoietin receptor (TPOR), known as MPL, a type I transmembrane receptor expressed on hematopoietic stem cells, megakaryocytes and platelets.[7]
CD34+ cells (2 × 104 cells/mL) purified from normal human cord blood (CB) were incubated in Iscove's Modified Dulbecco's Medium (IMDM) containing 20% foetal bovine serum (FBS) supplemented with 100 ng/mL recombinant human stem cell factor (rhSCF), and incubated with different concentrations of compounds for 7 days
Summary
Thrombocytopenia, characterized by abnormally low platelet counts in circulating blood, is caused by decreased platelet production and/ or accelerated platelet destruction. First‐generation TPOR agonists, such as recombinant human TPO (rhTPO) and PEGylated recombinant megakaryocyte growth and development factor (PEG‐rHuMGDF), have demonstrated efficacy in increasing platelet counts in the clinic.[5]. It has been reported that eltrombopag requires high daily dosing because of its low activity; this drug comes with a black box warning for potential hepatotoxicity, with elevated liver enzyme levels or clinical signs of liver damage.[17-19]. These observations highlight the desirability of developing small‐molecule TPOR agonists with improved efficacy and reduced toxicity. Hetrombopag enhanced the viability and promoted the growth of 32D‐MPL cells in hollow fibres implanted in nude mice, exhibiting much higher potency than eltrombopag in vivo
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call