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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2021

AutorInnen: Toutah, K; Nawar, N; Timonen, S; Sorger, H; Raouf, YS; Bukhari, S; von Jan, J; Ianevski, A; Gawel, JM; Olaoye, OO; Geletu, M; Abdeldayem, A; Israelian, J; Radu, TB; Sedighi, A; Bhatti, MN; Hassan, MM; Manaswiyoungkul, P; Shouksmith, AE; Neubauer, HA; de Araujo, ED; Aittokallio, T; Krämer, OH; Moriggl, R; Mustjoki, S; Herling, M; Gunning, PT

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

Quelle: J Med Chem. 2021;



Autor/innen der Vetmeduni Vienna:

Moriggl Richard
Neubauer Heidi
Sorger Helena

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik


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, 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.


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