2. Academic Validation
  3. A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction

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

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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