SH6

SH6 is a small-molecule degrader of the oncofetal transcription factor SALL4. SALL4 is a developmental protein that is typically silenced in adult tissues but frequently reactivated in various cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Research indicates that treatment with hypomethylating agents (HMAs) can paradoxically induce SALL4 expression through promoter demethylation, leading to treatment resistance and disease progression. SH6 is designed to induce the targeted degradation of the SALL4 protein, thereby inhibiting the oncogenic programs it facilitates. In preclinical models, SH6 has demonstrated the ability to reduce cell viability in SALL4-high leukemic cells and sensitize them to HMA therapy, suggesting its potential as a combination treatment to improve outcomes in patients with high-risk myeloid malignancies.