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Pharmacological Characterization of Hetrombopag, a Novel Orally Active Human Thrombopoietin Receptor Agonist

Pharmacological Characterization of Hetrombopag, a Novel Orally Active Human Thrombopoietin Receptor Agonist

Chengying Xie, Huajun Zhao, Xubin Bao, Haoyu Fu, Liguang Lou

J Cell Mol Med. 2018 Nov;22(11):5367-5377.

PMID: 30156363

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, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small-molecule TPOR agonist for patients with thrombocytopenia.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42412817	RB Active human			Price
IAR4248155	Bcl-xL Active human			Price

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