Discovery and\nOptimization of First-in-Class Molecular\nGlue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin\nInduction to Treat Sickle Cell Disease

Sickle cell disease (SCD) is a prevalent, life-threatening\ncondition\nwith few treatment options, attributed to a heritable mutation in\nβ-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF)\nwith small molecules has been pursued as a treatment to ameliorate\nmany disease complications but with limited success. Herein, we report\nthe discovery of <b>10</b>, a novel, potent, and selective molecular\nglue degrader of the transcription factor WIZ that robustly induces\nHbF expression as a potential treatment for SCD. <b>10</b> was\noptimized from a phenotypic screening hit utilizing insights from\nX-ray crystallography and computational modeling to improve potency,\nselectivity and <i>in vivo</i> exposure. In an hNBSGW mouse\nxenograft model, <b>10</b> demonstrated robust WIZ degradation\nand HbF induction. These results highlight the potential of WIZ degraders\nas a promising therapy for sickle cell disease.