Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of β-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure–activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of β-hemoglobinopathies, including SCD.

γ-珠蛋白基因的药理学活化可用于胎儿血红蛋白（HbF）的产生，是治疗β地中海贫血和镰状细胞疾病（SCD）的有前途的方法。我们在人类红系祖细胞中进行了表型筛选，以鉴定可诱导HbF的分子，从而鉴定出了命中化合物1。对结构-活性关系的探索和ADME性质的优化导致了2-azaspiro [3.3]庚烷衍生物18的形成，该衍生物更刚性且具有独特的结构。在体内使用食蟹猴，化合物18诱导了球蛋白转换的显着剂量依赖性增加，具有可开发的特性。此外，化合物18表现出没有遗传毒性作用，并且比羟基脲安全得多。这些发现可以促进开发包括SCD在内的治疗β-血红蛋白病的有效新疗法。