Abstract：
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.
摘要：
镰状细胞病(SCD)是一种普遍存在的疾病,可归因于β-血红蛋白可遗传突变的危及生命的疾病。胎儿血红蛋白（HbF）的治疗诱导可以改善疾病并发症，并且一直在努力追求。然而,安全有效的HbF小分子诱导剂仍然难以捉摸。我们报告了dWIZ-1和dWIZ-2的发现，它们是WIZ转录因子的分子胶降解物，它们强烈诱导成红细胞中的HbF。对小脑（CRBN）偏倚的化学文库的表型筛选显示，WIZ是先前未知的HbF阻遏物。WIZ降解是通过dWIZ-1将WIZ（ZF7）募集到CRBN来介导的，这通过三元络合物的晶体学来解决。WIZ的药理学降解在人源化小鼠和食蟹猴中具有良好的耐受性和诱导的HbF。这些发现将WIZ降解确立为SCD的全球可获得治疗策略。
