Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β-Thalassemia [WGBS]

The β-thalassemia is a recessively inherited disease affecting millions around the world. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy for the management of β-thalassemia. DNA methyltransferase inhibitors are effective HbF inducers, however was not currently approved for β-thalassemia treatments. Here we report that the newly developed non-nucleoside DNMT1 inhibitor DMT207 strongly reactivates the expression of HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. Moreover, in a mouse model of β-thalassemia, the administration of DMT207 effectively induces the expression of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly of mice. Further multi-omics studies expose γ-globin as one of the most sensitive genes in response to DMT207 treatment. Mechanistically, DMT207 inhibits DNMT1 enzymatic activity through trapping DNMT1 into an open conformation and meanwhile enhances interactions between the conformationally-kinked DNMT1 and UHRF1, partially contributing to specific degradation of DNMT1. Thus, we conclude that DMT207 is a promising novel DNMT1 inhibitor that could benefit patients with β-thalassemia.