Discovery of A Small Molecule Non-Imid Degrader of ZBTB7A for the Treatment of Β-Hemoglobinopathies

Sickle cell disease and β-thalassemia, two major β-hemoglobinopathies, pose significant clinical challenges globally. Current treatments often face limitations in efficacy and tolerability. The transcription factor ZBTB7A has emerged as a promising therapeutic target for reactivating fetal hemoglobin expression. Here, we report the discovery and characterization of SH6, a small molecule non-IMiD degrader of ZBTB7A. SH6 induces fetal hemoglobin in erythroid cell lines in a CRBN and ZBTB7A-dependent manner, and it is capable of inducing fetal hemoglobin expression in healthy donor, SCD and β-thalassemia patient CD34+ cell derived erythroid cells. The efficacy of SH6 is confirmed in a xenotransplantation humanized mouse model. SH6 outperforms currently available therapeutic agents in vitro , and shows synergy with hypomethylating agents. SH6 exhibits a favorable in vivo toxicity profile. Our findings establish SH6 as a promising therapeutic lead candidate for further optimization towards clinical development for treatment of sickle cell disease and β-thalassemia. ### Competing Interest Statement The authors have declared no competing interest. Cooley’s Anemia Foundation, https://ror.org/03hv05g61 United States Department of Defense, https://ror.org/0447fe631