A non-IMiD multi-target degrader reactivates fetal hemoglobin
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.
Authors
- Sarah Nikiforow (ORCID: https://orcid.org/0009-0001-2711-5575)
- Sean R. Stowell (ORCID: https://orcid.org/0000-0002-1130-9551)
- Jing Zeng (ORCID: https://orcid.org/0000-0002-4736-4210)
- Yi Zheng (ORCID: https://orcid.org/0000-0001-7089-6074)
- Po‐Shen Ko (ORCID: https://orcid.org/0000-0001-9299-0352)
- David G. Justus (ORCID: https://orcid.org/0000-0003-1345-0257)
- Kim Vanuytsel (ORCID: https://orcid.org/0000-0002-8872-0736)
- Kunhua Qin (ORCID: https://orcid.org/0000-0002-1388-2888)
- Sahand Hormoz (ORCID: https://orcid.org/0000-0002-4384-4428)
- Gerd A. Blobel (ORCID: https://orcid.org/0000-0002-0714-9612)
- John P. Manis (ORCID: https://orcid.org/0000-0002-3630-778X)
- Roger Belizaire (ORCID: https://orcid.org/0000-0001-8496-287X)
- Sophia Adamia (ORCID: https://orcid.org/0000-0001-5704-6040)
- Daniel Geoffrey Tenen (ORCID: https://orcid.org/0000-0002-6423-3888)
- Li Chai (ORCID: https://orcid.org/0000-0003-1937-4750)
- Wenhui Liu (ORCID: https://orcid.org/0009-0004-4465-4476)
- Shiva Moein (ORCID: https://orcid.org/0000-0002-6019-9504)
- Zhaoji Liu
- Daniel E. Bauer (ORCID: https://orcid.org/0000-0001-5076-7945)
- José A. Cancelas (ORCID: https://orcid.org/0000-0002-1291-7233)
- Christoph Budjan (ORCID: https://orcid.org/0000-0002-1563-9750)
- Hao Fan (ORCID: https://orcid.org/0000-0002-0822-1639)
- Hongbo Robert Luo (ORCID: https://orcid.org/0000-0002-8545-0451)
- Chong Gao (ORCID: https://orcid.org/0000-0001-7639-0808)
- Chaitanya Kumar Jaladanki (ORCID: https://orcid.org/0000-0001-5222-1137)
- Xi Tian
- Junsu Kwon (ORCID: https://orcid.org/0000-0002-6187-1366)
- Miao Liu (ORCID: https://orcid.org/0000-0003-3365-0213)
- Bo Liu (ORCID: https://orcid.org/0009-0007-3672-4894)
- Junyan Zhang (ORCID: https://orcid.org/0000-0001-8679-1373)
- Shin‐Young Park (ORCID: https://orcid.org/0000-0001-6385-4132)
- Ziyang Shen
- Jiajia Li (ORCID: https://orcid.org/0000-0002-8609-900X)
- Braden Pate (ORCID: https://orcid.org/0009-0002-5265-6530)
Institutions
- Boston University (US)
- Agency for Science, Technology and Research (SG)
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Boston Medical Center (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Bioinformatics Institute (SG)
- Harvard Stem Cell Institute (US)
- Cancer Science Institute of Singapore (SG)
Publication Details
- Journal
- Experimental Hematology and Oncology
- Published
- 2026-11-11
- DOI
- https://doi.org/10.1186/s40164-026-00846-5
- Citations
- 4
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 13.04