PTG-0861

Epigenetic targeting has emerged as an efficacious therapy for hematol. cancers.The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clin. course.Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy.Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematol. cancers.KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biol. activity, and a safe therapeutic window in nontransformed cell lines.In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biol. responses, and safety in healthy donor samples.Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax.Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.