A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction

• 成果类型: Article
• 署名作者: Ting, Pamela Y.; Borikar, Sneha; Kerrigan, John Ryan; Thomsen, Noel M.; Aghania, Eamon; Hinman, Amelia E.; Reyes, Alejandro; Pizzato, Nicolas; Fodor, Barna D.; Wu, Fabian; Belew, Muluken S.; Mao, Xiaohong; Wang, Jian; Chitnis, Shripad; Niu, Wei; Hachey, Amanda; Cobb, Jennifer S.; Savage, Nikolas A.; Burke, Ashley; Paulk, Joshiawa; Dovala, Dustin; Lin, James; Clifton, Matthew C.; Ornelas, Elizabeth; Ma, Xiaolei; Ware, Nathaniel F.; Sanchez, Carina C.; Taraszka, John; Terranova, Remi; Knehr, Judith; Altorfer, Marc; Barnes, S. Whitney; Beckwith, Rohan E. J.; Solomon, Jonathan M.; Dales, Natalie A.; Patterson, Andrew W.; Wagner, Juergen; Bouwmeester, Tewis; Dranoff, Glenn; Stevenson, Susan C.; Bradner, James E.
• 署名单位: Novartis; Novartis USA; Novartis; Novartis; Novartis USA; Novartis; Novartis USA; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Amgen
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11425
• DOI: 10.1126/science.adk6129
• 发表日期: 2024-07-05
• 页码: 91-99
• 关键词: sickle-cell-disease; g9a methyltransferase; degradation; pomalidomide; hydroxyurea; regulators; inhibition; therapy

摘要

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in beta-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.