Rafutrombopag (tautomerism)

Rafutrombopag (tautomerism) (Hetrombopag) is an orally active nonpeptide thrombopoietin receptor (TPOR/MPL) agonist. Rafutrombopag can chelate iron and alleviate iron overload while promoting haematopoiesis. Rafutrombopag specifically stimulates proliferation and differentiation of human TPOR‐expressing cells, including 32D‐ MPL and human hematopoietic stem cells through stimulation of STAT, PI3K and ERK signalling pathways. Rafutrombopag effectively up-regulates G1-phase-related proteins, including p-RB, Cyclin D1 and CDK4/6, normalizes progression of the cell cycle, and prevents apoptosis by modulating BCL-XL/BAK expression in 32D-MPL cells. Rafutrombopag protects cardiomyocyte survival from oxidative stress damage as an enhancer of stem cells. Rafutrombopag can be used for the study of immune thrombocytopenia and oxidative stress-related cardiovascular disease^[1][2][3]. In Vitro:Rafutrombopag (0.01-1000 nM, 0-7 days) stimulates intracellular TPO signalling pathways and promotes 32D-MPL (EC₅₀ = 0.4 nM) and BaF3/h TPOP ( EC₅₀ = 1.2 nM) cell proliferation in a TPOR-dependent manner^[1][2].
Rafutrombopag (0.01-10 μM, 0-10 days) promotes proliferation (EC₅₀ = 2.3 nM) and differentiation of human cord blood-derived CD34⁺ cells^[1][2].
Rafutrombopag (0-3 μM, 24-72 h) normalizes cell-cycle progression and prevents apoptosis in 32D-MPL cells and rat cardiac myocytes^[1].
Rafutrombopag (0.01-1000 nM, 30 min-72 h) interacts specifically with TPOR and exerts an additive agonistic effect with rhTPO^[1].
Rafutrombopag (0.3-3 μM, 12 h) enhances the beneficial effects of human UCB MNCs in increasing the survival of injured cardiomyocytes during free oxygen radical stress by enhancing human UCB MNCs viability and increasing the secretion of paracrine factors^[2].
Rafutrombopag (3-30 μM) has anti-inflammatory activity and significantly reduces the production of NO and TNF-a in LPS (HY-D1056) stimulated macrophage RAW264.7 cells^[2].
In Vivo:Rafutrombopag (18 mg/kg, p.o., single dose) exhibits the plasma concentration peaked at 687 ng/mL at 3 hours and decreases to 4.5 ng/mL at 24 hours, and the phosphorylation of STAT3, STAT5 and ERK1/2 is first detected at 3 hours, peaked at 6-12 hours, and lasted about 24 hours in mice^[1].
Rafutrombopag (18 mg/kg, p.o., once daily for 12 days) significantly stimulates proliferation and prevents apoptosis of 32D-MPL cells in hollow fibres in a time-dependent manner in mice^[1].