%0 Journal Article
%T A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
%A Ting PY
%A Borikar S
%A Kerrigan JR
%A Thomsen NM
%A Aghania E
%A Hinman AE
%A Reyes A
%A Pizzato N
%A Fodor BD
%A Wu F
%A Belew MS
%A Mao X
%A Wang J
%A Chitnis S
%A Niu W
%A Hachey A
%A Cobb JS
%A Savage NA
%A Burke A
%A Paulk J
%A Dovala D
%A Lin J
%A Clifton MC
%A Ornelas E
%A Ma X
%A Ware NF
%A Sanchez CC
%A Taraszka J
%A Terranova R
%A Knehr J
%A Altorfer M
%A Barnes SW
%A Beckwith REJ
%A Solomon JM
%A Dales NA
%A Patterson AW
%A Wagner J
%A Bouwmeester T
%A Dranoff G
%A Stevenson SC
%A Bradner JE
%J Science
%V 385
%N 6704
%D 2024 Jul 5
%M 38963839
%F 63.714
%R 10.1126/science.adk6129
%X 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.