S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)

Abstract

Background: S110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat b-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the g-globin gene promoter in vivo were evaluated. Methods: The effect of S110 on HbF and g-globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model. Results: S110 increased HbF and reduced DNA methylation of the g-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA. Conclusion: S110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.