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High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma

Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Garcha, Harsimran Kaur;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Nawar, Nabanita;
ORCID
0000-0002-3380-7770
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Sorger, Helena;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Erdogan, Fettah;
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Aung, Myint Myat Khine;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Sedighi, Abootaleb;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Manaswiyoungkul, Pimyupa;
Affiliation
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Seo, Hyuk-Soo;
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Schönefeldt, Susann;
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Pölöske, Daniel;
Affiliation
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Dhe-Paganon, Sirano;
ORCID
0000-0001-7372-7786
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Neubauer, Heidi A.;
ORCID
0000-0002-0816-8241
Affiliation
Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland
Mustjoki, Satu M.;
Affiliation
Department of Hematology, Cellular Therapy, and Hemostaseology, University of Leipzig, 04109 Leipzig, Germany
Herling, Marco;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
de Araujo, Elvin D.;
ORCID
0000-0003-0918-9463
Affiliation
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Moriggl, Richard;
Affiliation
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
Gunning, Patrick T.

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.

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