Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia
| Autor: | Patrick T. Gunning, Yasir S. Raouf, Muhammad Murtaza Hassan, Jana von Jan, Aleksandr Ianevski, Muzaffar N. Bhatti, Justyna M. Gawel, Mulu Geletu, Pimyupa Manaswiyoungkul, Nabanita Nawar, Elvin D. de Araujo, Helena Sorger, Olasunkanmi O. Olaoye, Tero Aittokallio, Oliver H. Krämer, Marco Herling, Sanna Timonen, Ayah Abdeldayem, Krimo Toutah, Tudor B. Radu, Richard Moriggl, Shazreh Bukhari, Johan Israelian, Heidi A. Neubauer, Satu Mustjoki, Andrew E. Shouksmith, Abootaleb Sedighi |
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| Přispěvatelé: | Computational Systems Medicine, TRIMM - Translational Immunology Research Program, Institute for Molecular Medicine Finland, Helsinki Institute for Information Technology, Tero Aittokallio / Principal Investigator, Bioinformatics, HUS Comprehensive Cancer Center, Department of Clinical Chemistry and Hematology, Clinicum |
| Rok vydání: | 2021 |
| Předmět: |
Male
Pyrrolidines medicine.medical_treatment TUBULIN Apoptosis SUBEROYLANILIDE HYDROXAMIC ACID Histone Deacetylase 6 Hydroxamic Acids 01 natural sciences Targeted therapy Mice chemistry.chemical_compound Drug Discovery para-Aminobenzoates Bendamustine Hydrochloride Prolymphocytic leukemia RICOLINOSTAT Sulfonamides 0303 health sciences Molecular Structure Chemistry Drug Synergism 3. Good health Molecular Docking Simulation Molecular Medicine medicine.drug Bendamustine ACCURATE DOCKING EXPRESSION 3122 Cancers BORTEZOMIB Antineoplastic Agents BCL-2 INHIBITOR Article Structure-Activity Relationship 03 medical and health sciences HISTONE DEACETYLASE INHIBITOR Cell Line Tumor medicine Animals Humans Epigenetics COMBINATION 030304 developmental biology Venetoclax HDAC6 Bridged Bicyclo Compounds Heterocyclic medicine.disease 0104 chemical sciences Histone Deacetylase Inhibitors MODEL 010404 medicinal & biomolecular chemistry Leukemia Prolymphocytic T-Cell Cancer research T-cell prolymphocytic leukemia Histone deacetylase |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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