Catalog Number
ACM1257792418
Description
Hetrombopag is an orally active human thrombopoietin receptor agonist. Hetrombopag protects Cardiomyocyte Survival from Oxidative Stress Damage as an Enhancer of Stem Cells. 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.
Synonyms
SHR8735; SHR 8735; SHR-8735; Hetrombopag
IUPAC Name
(E)-5-(2-hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazinyl)phenyl)furan-2-carboxylic acid
Molecular Formula
C25H22N4O5
Canonical SMILES
O=C(C1=CC=C(C2=CC=CC(N/N=C3C(N(C4=CC=C5CCCCC5=C4)N=C/3C)=O)=C2O)O1)O
InChI
InChI=1S/C25H22N4O5/c1-14-22(24(31)29(28-14)17-10-9-15-5-2-3-6-16(15)13-17)27-26-19-8-4-7-18(23(19)30)20-11-12-21(34-20)25(32)33/h4,7-13,26,30H,2-3,5-6H2,1H3,(H,32,33)/b27-22+
InChI Key
BDGGFTDRPHKXFC-HPNDGRJYSA-N
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Storage
Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
Alternative CAS
1257792-41-8 (free acid); 1257792-41-8 (ethanolamine); 1257792-42-9 (olamine)
Biological Target
Hetrombopag is an orally active human thrombopoietin receptor agonist that protects cardiomyocyte survival from oxidative stress damage as an enhancer of stem cells.
Drug Formulation
This drug may be formulated in DMSO
Elemental Analysis
C, 65.49; H, 4.84; N, 12.22; O, 17.45
HS Tariff Code
2934.99.9001
In Vitro Activity
Accordingly, the effect of hetrombopag on megakaryopoiesis in TPOR-positive human CB-derived CD34+ cells, used as a source of hematopoietic stem cells, was investigated. Hetrombopag stimulated the proliferation of human CB-derived CD34+ cells, with an EC50 value of 2.3 nmol/L. The total number of MK (CD41+) increased after treated with hetrombopag n a concentration-dependent manner, with an EC50 value of 4.5 nmol/L. The percentage of mature MK (CD41+/CD42a+) also increased after treatment with hetrombopag. As expected, hetrombopag stimulated MK proplatelet formation from human CB-CD34+ cells in vitro. Corresponding to its MK-stimulating activity, hetrombopag induced a concentration-dependent increase in the phosphorylation of STAT3, STAT5 and ERK1/2 in human CB CD34+ cells, exerting a much stronger effect than eltrombopag. Taken together, these results suggest that hetrombopag is capable of stimulating the proliferation and differentiation of megakaryocyte progenitor cells, and then proplatelet production via TPOR signalling.
Reference: J Cell Mol Med. 2018 Nov;22(11):5367-5377. https://pubmed.ncbi.nlm.nih.gov/30156363/
In Vivo Activity
A once-daily dosing regimen in nude mice subcutaneously implanted with hollow fibres containing 32D-MPL cells was used to investigate the efficacy of hetrombopag in vivo. Daily oral administration of 18 mg/kg hetrombopag for 12 days significantly stimulated proliferation and prevented apoptosis of 32D-MPL cells in hollow fibres in a time-dependent manner. The number of 32D-MPL cells reached a maximum after 3 days of daily oral administration of hetrombopag, and then decreased within 12 days. In contrast, few live cells were present in hollow fibres in the vehicle group after 3 days of treatment. The in vivo efficacy of hetrombopag was also dose-dependent, and was significant at doses of 6 mg/kg or greater (P < 0.01).
Reference: J Cell Mol Med. 2018 Nov;22(11):5367-5377. https://pubmed.ncbi.nlm.nih.gov/30156363/
Shipping
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Stock Solution Storage
0-4 °C for short term (days to weeks), or -20 °C for long term (months).
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