Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as β-thalassemia and SCD.

有人建议通过治疗药物重新激活胎儿血红蛋白 (HbF) 表达作为调节贫血以及严重 β 地中海贫血和镰状细胞病 (SCD) 相关症状的替代疗法。羟基脲 (HU) 是美国 FDA 批准的第一个用于治疗 SCD 的 HbF 诱导剂。然而，大约 25% 的 SCD 患者对 HU 没有反应。先前的一项研究确定 TN1 ( 1 ) 是一种小分子 HbF 诱导剂。然而，这项研究发现化合物1的效力和口服生物利用度较差，限制了该诱导剂的临床应用开发。为了开发药物样化合物，对1的嘌呤结构进行了进一步的构效关系研究。在此，我们报告了一种更有效的诱导剂化合物13a的发现，它可以在非细胞毒性浓度下有效诱导 γ-珠蛋白基因表达。还研究了13a调节 HbF 表达的分子机制。此外，我们证明口服13a可以改善 SCD 小鼠的贫血和相关症状。这项研究的结果表明， 13a可以进一步开发为治疗血红蛋白病（如 β 地中海贫血和 SCD）的新型药物。