RK-701 is an highly selective and non-genotoxic inhibitor of G9a with IC50 value of 23-27 nM. RK-701 selectively up-regulates HbF, γ- Globin, BGLT3 expression, down-regulates H3K9me2 expression. RK-701 also has inhibition for BCL11A and ZBTB7A.
RK-701 (0.01-3 µM; 4 d) up-regulates the expression level of HbF and γ-globin mRNA without affecting cell viability or erythroid differentiation. RK-701 increases the proportion of HbF expressing cells in a concentration-dependent manner. In HUDEP-2 cells and human primary CD34+ cells, RK-701 also selectively up-regulates the expression level of BGLT3 and reduces the proportion of H3K9me2 in β-globin[1].RK-701 (1 µM; 4 d) significantly reduces the proportion of BCL11A and ZBTB7A in BGLT3 without increasing the expression of BGLT3 in HUDEP-2 cells under the absence of BCL11A or ZBTB7A[1].
RK-701 (20 mg/kg and 50 mg/kg; i.p.; 5 weeks, each week for 5 consecutive days) selectively increases mouse embryos ε Y-globin and significantly down-regulates the expression level of H3K9me2 in peripheral blood cells. RK-701 has low toxicity[1].
References:
[1]. Takase S, et al. A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression. Nat Commun. 2023 Jan 12;14(1):23.