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

  • Science. 2024 Jul 5;385(6704):91-99. doi: 10.1126/science.adk6129.
Pamela Y Ting  1 ,  Sneha Borikar  1 ,  John Ryan Kerrigan  1 ,  Noel M Thomsen  1 ,  Eamon Aghania  1 ,  Amelia E Hinman  1 ,  Alejandro Reyes  2 ,  Nicolas Pizzato  2 ,  Barna D Fodor  2 ,  Fabian Wu  2 ,  Muluken S Belew  1 ,  Xiaohong Mao  1 ,  Jian Wang  1 ,  Shripad Chitnis  1 ,  Wei Niu  1 ,  Amanda Hachey  1 ,  Jennifer S Cobb  1 ,  Nikolas A Savage  1 ,  Ashley Burke  1 ,  Joshiawa Paulk  1 ,  Dustin Dovala  3 ,  James Lin  3 ,  Matthew C Clifton  3 ,  Elizabeth Ornelas  3 ,  Xiaolei Ma  3 ,  Nathaniel F Ware  1 ,  Carina C Sanchez  1 ,  John Taraszka  1 ,  Remi Terranova  2 ,  Judith Knehr  2 ,  Marc Altorfer  2 ,  S Whitney Barnes  4 ,  Rohan E J Beckwith  1 ,  Jonathan M Solomon  1 ,  Natalie A Dales  1 ,  Andrew W Patterson  1 ,  Jürgen Wagner  2 ,  Tewis Bouwmeester  2 ,  Glenn Dranoff  1 ,  Susan C Stevenson  1 ,  James E Bradner  1
Affiliations
  • 1. Novartis Biomedical Research, Cambridge, MA, USA.
  • 2. Novartis Biomedical Research, Basel, Switzerland.
  • 3. Novartis Biomedical Research, Emeryville, CA, USA.
  • 4. Novartis Biomedical Research, San Diego, CA, USA.
PMID: 38963839 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.

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