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