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

Krimo Toutah, Nabanita Nawar, Sanna Timonen, Helena Sorger, Yasir S. Raouf, Shazreh Bukhari, Jana von Jan, Aleksandr Ianevski, Justyna M. Gawel, Olasunkanmi O. Olaoye, Mulu Geletu, Ayah Abdeldayem, Johan Israelian, Tudor B. Radu, Abootaleb Sedighi, Muzaffar N. Bhatti, Muhammad Murtaza Hassan, Pimyupa Manaswiyoungkul, Andrew E. Shouksmith, Heidi A. NeubauerElvin D. de Araujo, Tero Aittokallio, Oliver H. Krämer, Richard Moriggl, Satu Mustjoki, Marco Herling, Patrick T. Gunning

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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, whereHDAC6was 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.

Original languageEnglish
Pages (from-to)8486-8509
Number of pages24
JournalJournal of Medicinal Chemistry
Volume64
Issue number12
DOIs
Publication statusPublished - Jun 24 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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