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Title (en)
High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma
Language
English
Description (en)
NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies.
Keywords (en)
T-Cell Lymphoma; Histone Deacetylase Inhibitor; Refinement; Therapy; Tubulin; Cancer; Hdac6; Features; Assay
DOI
10.3390/ph15111321
Author of the digital object
Harsimran Kaur Garcha  (University of Toronto)
Patrick T. Gunning  (University of Toronto)
Richard Moriggl  (University of Veterinary Medicine Vienna)
Elvin D. de Araujo  (University of Toronto)
Marco Herling  (University of Leipzig)
Satu M Mustjoki  (University of Helsinki / Helsinki University Hospital Comprehensive Cancer Center)
Heidi A. Neubauer  (University of Veterinary Medicine Vienna)
Sirano Dhe-Paganon  (Dana-Farber Cancer Institute / Harvard Medical School)
Daniel Pölöske  (University of Veterinary Medicine Vienna)
Susann Schönefeldt  (University of Veterinary Medicine Vienna)
Hyuk-Soo Seo  (Dana-Farber Cancer Institute / Harvard Medical School)
Pimyupa Manaswiyoungkul  (University of Toronto)
Abootaleb Sedighi  (University of Toronto)
Myint Myat Khine Aung  (University of Veterinary Medicine Vienna)
Fettah Erdogan  (University of Toronto)
Nabanita Nawar  (University of Toronto)
Helena Sorger  (University of Veterinary Medicine Vienna)
Format
application/pdf
Size
929.8 kB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
Pharmaceuticals
Pages or Volume
20
Volume
15
Number
11
Publisher
MDPI
Publication Date
2022