SF2-69

SF2-69 is a selective small-molecule inhibitor of Poly(U) Binding Splicing Factor 60 (PUF60), a protein involved in 3' splice site selection during RNA splicing. Developed by researchers at the University of Tennessee Health Science Center and the Cleveland Clinic, SF2-69 targets the U2 homology motif (UHM) domain of PUF60. It demonstrates over 15-fold selectivity for PUF60 over related splicing factors such as U2AF1, RBM39, SPF45, and U2AF2. In leukemia models, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), SF2-69 exhibits anti-leukemic activity by disrupting cell cycle progression, inducing S and subG1 phase accumulation or G1 arrest depending on the p53 status of the cells. It was optimized from a weaker precursor, SF-153, to serve as a potential therapeutic lead for myeloid neoplasms carrying splicing factor mutations.