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

Autor: 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.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Jul 05; Vol. 385 (6704), pp. 91-99. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1126/science.adk6129
Abstrakt: 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.
Databáze: MEDLINE
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