Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

中文翻译：

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发现和优化用于胎儿血红蛋白诱导治疗镰状细胞病的 WIZ 转录因子的一流分子胶降解剂


镰状细胞病 （SCD） 是一种普遍的、危及生命的疾病，几乎没有治疗选择，归因于 β-血红蛋白的遗传突变。用小分子治疗性诱导胎儿血红蛋白 （HbF） 已被作为改善许多疾病并发症的治疗方法，但成功率有限。在此，我们报道了 10 的发现，这是一种新型、有效且选择性的转录因子 WIZ 分子胶降解剂，可强烈诱导 HbF 表达作为 SCD 的潜在治疗方法。10 利用 X 射线晶体学和计算建模的见解从表型筛选命中进行了优化，以提高效力、选择性和体内暴露。在 hNBSGW 小鼠异种移植模型中，10 个表现出强大的 WIZ 降解和 HbF 诱导。这些结果突出了 WIZ 降解剂作为镰状细胞病有前途的疗法的潜力。