A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
Science
; 385(6704): 91-99, 2024 Jul 05.
Article
em En
| MEDLINE
| ID: mdl-38963839
ABSTRACT
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hemoglobina Fetal
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Fatores de Transcrição Kruppel-Like
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Anemia Falciforme
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Proteínas do Tecido Nervoso
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Antidrepanocíticos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article