Zeitschriftenaufsatz | 2021 Open Access

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

Autor:in

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

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Neubauer-Sedy, Heidi

Journal

Journal Of Medicinal Chemistry

Abstrakt

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 standalone or in combination with targeted drugs.

Schlagwörter

Animals; Antineoplastic Agentschemical synthesispharmacokineticstherapeutic use; Apoptosisdrug effects; Bendamustine Hydrochloridepharmacology; Bridged Bicyclo Compounds, Heterocyclicpharmacology; Cell Line, Tumor; Drug Synergism; Histone Deacetylase 6metabolism; Histone Deacetylase Inhibitorschemical synthesispharmacokineticstherapeutic use; Humans; Hydroxamic Acidschemical synthesispharmacokineticstherapeutic use; Leukemia, Prolymphocytic, T-Celldrug therapy; Male; Mice; Molecular Docking Simulation; Molecular Structure; Pyrrolidinespharmacology; Structure-Activity Relationship; Sulfonamideschemical synthesispharmacokineticspharmacologytherapeutic use; para-Aminobenzoatespharmacology

Dokumententyp

Originalarbeit

CC Lizenz

CCBY

Open Access Type

Hybrid

ISSN/eISSN

0022-2623 - 1520-4804

DOI

10.1021/acs.jmedchem.1c00420