研究人员表示，镰状细胞病（SCD）是一种常见且危及生命的疾病，由β-血红蛋白的遗传突变引起。治疗性诱导胎儿血红蛋白（HbF）可以缓解疾病并发症，一直备受关注。然而，安全有效的HbF小分子诱导剂仍然难以找到。
研究人员报告了dWIZ-1和dWIZ-2的发现，这些是WIZ转录因子的分子胶水降解剂，能够在红细胞母细胞中强效诱导HbF。对一个偏向cereblon（CRBN）的化学库进行表型筛选，研究人员发现WIZ是以前未知的HbF抑制因子。WIZ降解是通过dWIZ-1将WIZ(ZF7)招募到CRBN来介导的，这一机制通过三元复合物的晶体结构得以解析。WIZ的药理降解在人源化小鼠和食蟹猴中均耐受良好，并诱导了HbF。这些发现确立了WIZ降解作为SCD的一种全球可及的治疗策略。
附：英文原文
Title: A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction
Author: Pamela Y. Ting, Sneha Borikar, John Ryan Kerrigan, Noel M. Thomsen, Eamon Aghania, Amelia E. Hinman, Alejandro Reyes, Nicolas Pizzato, Barna D. Fodor, Fabian Wu, Muluken S. Belew, Xiaohong Mao, Jian Wang, Shripad Chitnis, Wei Niu, Amanda Hachey, Jennifer S. Cobb, Nikolas A. Savage, Ashley Burke, Joshiawa Paulk, Dustin Dovala, James Lin, Matthew C. Clifton, Elizabeth Ornelas, Xiaolei Ma, Nathaniel F. Ware, Carina C. Sanchez, John Taraszka, Remi Terranova, Judith Knehr, Marc Altorfer, S. Whitney Barnes, Rohan E. J. Beckwith, Jonathan M. Solomon, Natalie A. Dales, Andrew W. Patterson, Jürgen Wagner, Tewis Bouwmeester, Glenn Dranoff, Susan C. Stevenson, James E. Bradner
Issue&Volume: 2024-07-05
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.
DOI: adk6129
Source: https://www.science.org/doi/10.1126/science.adk6129