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A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
Ting, Pamela Y; Borikar, Sneha; Kerrigan, John Ryan; Thomsen, Noel M; Aghania, Eamon; Hinman, Amelia E; Reyes, Alejandro; Pizzato, Nicolas; Fodor, Barna D; Wu, Fabian; Belew, Muluken S; Mao, Xiaohong; Wang, Jian; Chitnis, Shripad; Niu, Wei; Hachey, Amanda; Cobb, Jennifer S; Savage, Nikolas A; Burke, Ashley; Paulk, Joshiawa; Dovala, Dustin; Lin, James; Clifton, Matthew C; Ornelas, Elizabeth; Ma, Xiaolei; Ware, Nathaniel F; Sanchez, Carina C; Taraszka, John; Terranova, Remi; Knehr, Judith; Altorfer, Marc; Barnes, S Whitney; Beckwith, Rohan E J; Solomon, Jonathan M; Dales, Natalie A; Patterson, Andrew W; Wagner, Jürgen; Bouwmeester, Tewis; Dranoff, Glenn; Stevenson, Susan C; Bradner, James E.
Afiliación
  • Ting PY; Novartis Biomedical Research, Cambridge, MA, USA.
  • Borikar S; Novartis Biomedical Research, Cambridge, MA, USA.
  • Kerrigan JR; Novartis Biomedical Research, Cambridge, MA, USA.
  • Thomsen NM; Novartis Biomedical Research, Cambridge, MA, USA.
  • Aghania E; Novartis Biomedical Research, Cambridge, MA, USA.
  • Hinman AE; Novartis Biomedical Research, Cambridge, MA, USA.
  • Reyes A; Novartis Biomedical Research, Basel, Switzerland.
  • Pizzato N; Novartis Biomedical Research, Basel, Switzerland.
  • Fodor BD; Novartis Biomedical Research, Basel, Switzerland.
  • Wu F; Novartis Biomedical Research, Basel, Switzerland.
  • Belew MS; Novartis Biomedical Research, Cambridge, MA, USA.
  • Mao X; Novartis Biomedical Research, Cambridge, MA, USA.
  • Wang J; Novartis Biomedical Research, Cambridge, MA, USA.
  • Chitnis S; Novartis Biomedical Research, Cambridge, MA, USA.
  • Niu W; Novartis Biomedical Research, Cambridge, MA, USA.
  • Hachey A; Novartis Biomedical Research, Cambridge, MA, USA.
  • Cobb JS; Novartis Biomedical Research, Cambridge, MA, USA.
  • Savage NA; Novartis Biomedical Research, Cambridge, MA, USA.
  • Burke A; Novartis Biomedical Research, Cambridge, MA, USA.
  • Paulk J; Novartis Biomedical Research, Cambridge, MA, USA.
  • Dovala D; Novartis Biomedical Research, Emeryville, CA, USA.
  • Lin J; Novartis Biomedical Research, Emeryville, CA, USA.
  • Clifton MC; Novartis Biomedical Research, Emeryville, CA, USA.
  • Ornelas E; Novartis Biomedical Research, Emeryville, CA, USA.
  • Ma X; Novartis Biomedical Research, Emeryville, CA, USA.
  • Ware NF; Novartis Biomedical Research, Cambridge, MA, USA.
  • Sanchez CC; Novartis Biomedical Research, Cambridge, MA, USA.
  • Taraszka J; Novartis Biomedical Research, Cambridge, MA, USA.
  • Terranova R; Novartis Biomedical Research, Basel, Switzerland.
  • Knehr J; Novartis Biomedical Research, Basel, Switzerland.
  • Altorfer M; Novartis Biomedical Research, Basel, Switzerland.
  • Barnes SW; Novartis Biomedical Research, San Diego, CA, USA.
  • Beckwith REJ; Novartis Biomedical Research, Cambridge, MA, USA.
  • Solomon JM; Novartis Biomedical Research, Cambridge, MA, USA.
  • Dales NA; Novartis Biomedical Research, Cambridge, MA, USA.
  • Patterson AW; Novartis Biomedical Research, Cambridge, MA, USA.
  • Wagner J; Novartis Biomedical Research, Basel, Switzerland.
  • Bouwmeester T; Novartis Biomedical Research, Basel, Switzerland.
  • Dranoff G; Novartis Biomedical Research, Cambridge, MA, USA.
  • Stevenson SC; Novartis Biomedical Research, Cambridge, MA, USA.
  • Bradner JE; Novartis Biomedical Research, Cambridge, MA, USA.
Science ; 385(6704): 91-99, 2024 Jul 05.
Article en 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemoglobina Fetal / Factores de Transcripción de Tipo Kruppel / Anemia de Células Falciformes / Proteínas del Tejido Nervioso / Antidrepanocíticos Límite: Animals / Humans Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemoglobina Fetal / Factores de Transcripción de Tipo Kruppel / Anemia de Células Falciformes / Proteínas del Tejido Nervioso / Antidrepanocíticos Límite: Animals / Humans Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos