# Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β‐Thalassemia

## TL;DR

Scientists discovered a new drug, DMT207, that effectively treats β-thalassemia by boosting fetal hemoglobin with minimal side effects.

## Contribution

DMT207, a novel DNMT1 inhibitor, shows improved efficacy and safety for β-thalassemia treatment compared to existing drugs.

## Key findings

- DMT207 reactivates fetal hemoglobin in human cells and mouse models of β-thalassemia.
- DMT207 reduces spleen enlargement and promotes erythroid cell maturation in β-thalassemia mice.
- DMT207 induces DNMT1 inactivation and degradation, targeting γ-globin genes specifically.

## Abstract

β‐thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although effective HbF inducers, currently are not approved for β‐thalassemia treatment. Here, we report that DMT207, a novel non‐nucleoside DNMT1 inhibitor, robustly reactivates HbF in HUDEP‐2 cells and adult primary erythroblasts with minimal toxicity. In a mouse model of β‐thalassemia, DMT207 effectively elevates the levels of mouse fetal‐ and embryonic‐type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly. Further multi‐omics analyses expose γ‐globin as one of the most sensitive genes with promoter demethylation and transcriptional activation following DMT207 treatment. Mechanistically, DMT207 traps DNMT1 into a catalytically inactive conformation and concurrently enhances its interaction with UHRF1, which partially contributes to DNMT1 degradation. These findings highlight the therapeutic potential of DMT207 for β‐thalassemia and support its further preclinical development.

Context of Research: β‐thalassemia affects millions worldwide. DNMT inhibitors are effective HbF‐inducers that benefit patients with β‐thalassemia. Existing DNMT inhibitors are not approved for β‐thalassemia treatment due to dose‐limiting toxicity.

What We Find: DMT207 traps DNMT1 into helix‐kinked inactive conformation and enhances its interaction with UHRF1. DMT207 potently induces HbF in vitro and in vivo, alleviating β‐thalassemia‐associated symptoms in mice with well tolerability. Multi‐omics analyses reveal HBG1/2 as highly responsive targets, while global gene expression remains stable, suggesting specificity and safety.