A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
Pamela Y TingSneha BorikarJohn Ryan KerriganNoel M ThomsenEamon AghaniaAmelia E HinmanAlejandro ReyesNicolas PizzatoBarna D FodorFabian WuMuluken S BelewXiaohong MaoJian WangShripad ChitnisWei NiuAmanda HacheyJennifer S CobbNikolas A SavageAshley BurkeJoshiawa PaulkDustin DovalaJames LinMatthew C CliftonElizabeth OrnelasXiaolei MaNathaniel F WareCarina C SanchezJohn TaraszkaRemi TerranovaJudith KnehrMarc AltorferS Whitney BarnesRohan E J BeckwithJonathan M SolomonNatalie A DalesAndrew W PattersonJuergen WagnerTewis BouwmeesterGlenn DranoffSusan C StevensonJames E BradnerPublished in: Science (New York, N.Y.) (2024)
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.