Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

Liu, J.; Shen, Z.; Park, S.-Y.; Dong, Y.; Yu, N.; Zeng, J.; Lee, H.; Pate, B.; Adamia, S.; Vanuytsel, K.; Zhang, J.; Wu, S.-C.; Herman, A.; Moein, S.; Liu, W.; Liu, M.; Gao, C.; Tian, X.; Liu, Z.; Kwon, J.; Qin, K.; Budjan, C.; Ko, P.-S.; Shao, C.; Jaladanki, C. K.; Li, J.; Lee, E.; Liu, B.-h.; Stowell, S.; Manis, J. P.; Justus, D.; Blobel, G. A.; Luo, H. R.; Belizaire, R.; Zheng, Y.; Hormoz, S.; Nikiforow, S.; Cancelas, J. A.; Fan, H.; Bauer, D. E.; Tenen, D. G.; Chai, L.

doi:10.1101/2025.09.17.676148

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bioRxiv · 10.1101/2025.09.17.676148

Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

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Abstract

Sickle cell disease and {beta}-thalassemia, two major {beta}-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 {beta}-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 {beta}-thalassemia.

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Liu, J., Shen, Z., Park, S.-Y., Dong, Y., Yu, N., Zeng, J., Lee, H., Pate, B., Adamia, S., Vanuytsel, K., Zhang, J., Wu, S.-C., Herman, A., Moein, S., Liu, W., Liu, M., Gao, C., Tian, X., Liu, Z., Kwon, J., Qin, K., Budjan, C., Ko, P.-S., Shao, C., Jaladanki, C. K., Li, J., Lee, E., Liu, B.-h., Stowell, S., Manis, J. P., Justus, D., Blobel, G. A., Luo, H. R., Belizaire, R., Zheng, Y., Hormoz, S., Nikiforow, S., Cancelas, J. A., Fan, H., Bauer, D. E., Tenen, D. G., Chai, L.. 2025-09-17. Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies. https://doi.org/10.1101/2025.09.17.676148

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