Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T‑Cell Prolymphocytic Leukemia

Epigenetic targeting
has emerged as an efficacious therapy for
hematological cancers. The rare and incurable T-cell prolymphocytic
leukemia (T-PLL) is known for its aggressive clinical 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 hematological
cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity,
on-target biological 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 biological
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.