A non-IMiD multi-target degrader reactivates fetal hemoglobin.

Abstract

Reactivation of fetal hemoglobin (HbF) is a validated therapeutic strategy for sickle cell disease (SCD) and β-thalassemia. Cereblon (CRBN)-dependent molecular-glue degraders of HbF repressors are advancing clinically, but all share an immunomodulatory imide drug (IMiD) backbone and its class liabilities. We show that SH6, a non-IMiD small-molecule degrader, consistently induces HbF in erythroid cell lines, primary healthy-donor, SCD, and β-thalassemia CD34⁺-derived erythroid cells, and humanized NBSGW mice, at nanomolar to low-micromolar concentrations. When all compounds were tested at a matched 0.25µM concentration, HbF induction by SH6 was comparable to that of decitabine and greater than that of hydroxyurea, pomalidomide or thalidomide. HbF induction is CRBN/proteasome-dependent and associated with simultaneous degradation of the γ-globin repressors ZBTB7A and BCL11A. These findings provide proof of concept for IMiD-independent pharmacologic HbF reactivation and support further study of SH6 as a mechanistically distinct tool compound.

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