Increased expression of fetal hemoglobin (HbF) improves the clinical severity of β-thalassemia patients. EHMT1/2 histone methyltransferases are epigenetic modifying enzymes that are responsible for catalyzing addition of the repressive histone mark H3K9me2 at silenced genes, including the γ-globin genes. UNC0638, a chemical inhibitor of EHMT1/2, has been shown to induce HbF expression in human erythroid progenitor cell cultures. Here, we report the HbF-inducing activity of UNC0638 in erythroid progenitor cells from β-thalassemia/HbE patients. UNC0638 treatment led to significant increases in γ-globin mRNA, HbF expression, and HbF-containing cells in the absence of significant cytotoxicity. Moreover, UNC0638 showed additive effects on HbF induction in combination with the immunomodulatory drug pomalidomide and the DNMT1 inhibitor decitabine. These studies provide a scientific proof of concept that a small molecule targeting EHMT1/2 epigenetic enzymes, used alone or in combination with pomalidomide or decitabine, is a potential therapeutic approach for HbF induction. Further development of structural analogs of UNC0638 with similar biological effects but improved pharmacokinetic properties may lead to promising therapies and possible clinical application for the treatment of β-thalassemia.

胎儿血红蛋白（HbF）的表达增加可改善β地中海贫血患者的临床严重程度。EHMT1 / 2组蛋白甲基转移酶是表观遗传修饰酶，负责催化沉默基因（包括γ-珠蛋白基因）上的组蛋白标记H3K9me2加成。UNC0638是EHMT1 / 2的化学抑制剂，已显示出可在人红系祖细胞培养物中诱导HbF表达。在此，我们报道了来自β地中海贫血/ HbE患者的类红细胞祖细胞中UNC0638的HbF诱导活性。在没有明显细胞毒性的情况下，UNC0638处理导致γ-球蛋白mRNA，HbF表达和含HbF的细胞显着增加。此外，UNC0638与免疫调节药物波马利度胺和DNMT1抑制剂地西他滨合用对HbF的诱导具有累加作用。这些研究提供了概念上的科学证据，即单独或与pomalidomide或地西他滨组合使用的靶向EHMT1 / 2表观遗传酶的小分子是诱导HbF的潜在治疗方法。UNC0638结构类似物的进一步开发具有相似的生物学效应，但药代动力学特性得到改善，可能导致有希望的疗法和可能的临床应用，以治疗β地中海贫血。