Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease

Sickle cell disease (SCD) is a prevalent, life-threatening
condition
with few treatment options, attributed to a heritable mutation in
β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF)
with small molecules has been pursued as a treatment to ameliorate
many disease complications but with limited success. Herein, we report
the discovery of 10, a novel, potent, and selective molecular
glue degrader of the transcription factor WIZ that robustly induces
HbF expression as a potential treatment for SCD. 10 was
optimized from a phenotypic screening hit utilizing insights from
X-ray crystallography and computational modeling to improve potency,
selectivity and in vivo exposure. In an hNBSGW mouse
xenograft model, 10 demonstrated robust WIZ degradation
and HbF induction. These results highlight the potential of WIZ degraders
as a promising therapy for sickle cell disease.