Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist

Journal of Cellular and Molecular Medicine
Cheng-Ying XieLiguang Lou

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 EC50 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...Continue Reading

References

Sep 2, 1994·Science·A L GurneyM W Moore
Feb 1, 1996·The Journal of Experimental Medicine·F J de SauvageM W Moore
May 1, 1999·The Journal of Biological Chemistry·J G DrachmanK Kaushansky
Jun 24, 2004·Seminars in Cell & Developmental Biology·Julian Downward
Sep 30, 2006·Transfusion Medicine Reviews·Marloes R TijssenJaap Jan Zwaginga
Mar 1, 2007·Blood·Julian M JenkinsConnie L Erickson-Miller
Mar 27, 2007·Cell·Kylie D MasonBenjamin T Kile
Nov 30, 2007·The New England Journal of Medicine·James B BusselJulian M Jenkins
Jan 24, 2009·Journal of Natural Products·Qiuwen MiSteven M Swanson
Jul 31, 2009·Annual Review of Medicine·David J Kuter
Nov 19, 2010·Expert Review of Hematology·Elizabeth Rhodes, Roberto Stasi
Sep 14, 2011·The Journal of Experimental Medicine·Emma C JosefssonBenjamin T Kile
Aug 9, 2012·Current Opinion in Hematology·Paul A Basciano, James B Bussel
Sep 18, 2012·International Journal of Technology Assessment in Health Care·Katy L CooperRon Akehurst
Sep 19, 2014·International Journal of Hematology·Caizheng Li, Li Zheng
May 26, 2017·Basic & Clinical Pharmacology & Toxicology·Li ZhengAn-Bo Xiang

❮ Previous
Next ❯

Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
Flow

Software Mentioned

GraphPad
ModFit LT Mac
GraphPad Prism

Related Concepts

Related Feeds

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.