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.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Anemia, Sickle Cell* / drug therapy
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Anemia, Sickle Cell* / metabolism
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Animals
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Antisickling Agents* / chemistry
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Antisickling Agents* / pharmacology
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Antisickling Agents* / therapeutic use
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Crystallography, X-Ray
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Drug Discovery
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Fetal Hemoglobin* / genetics
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Fetal Hemoglobin* / metabolism
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Humans
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Kruppel-Like Transcription Factors* / metabolism
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Macaca fascicularis
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Mice
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Nerve Tissue Proteins* / metabolism
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Proteolysis / drug effects
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Small Molecule Libraries / therapeutic use
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antisickling Agents
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CRBN protein, human
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Fetal Hemoglobin
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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Small Molecule Libraries
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Ubiquitin-Protein Ligases
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Wiz protein, mouse