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

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

  • Pharmaceuticals (Basel). 2022 Oct 26;15(11):1321. doi: 10.3390/ph15111321.
Harsimran Kaur Garcha 1 2,  Nabanita Nawar 1 2,  Helena Sorger 3,  Fettah Erdogan 1 2,  Myint Myat Khine Aung 3,  Abootaleb Sedighi 1,  Pimyupa Manaswiyoungkul 1 2,  Hyuk-Soo Seo 4 5,  Susann Schönefeldt 3,  Daniel Pölöske 3,  Sirano Dhe-Paganon 4 5,  Heidi A Neubauer 3,  Satu M Mustjoki 6 7 8,  Marco Herling 9,  Elvin D de Araujo 1,  Richard Moriggl 3,  Patrick T Gunning 1 2
Affiliations

Affiliations

  • 1 Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
  • 2 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada.
  • 3 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 6 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland.
  • 7 Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland.
  • 8 iCAN Digital Precision Cancer Medicine Flagship, 00014 Helsinki, Finland.
  • 9 Department of Hematology, Cellular Therapy, and Hemostaseology, University of Leipzig, 04109 Leipzig, Germany.
PMID: 36355493 DOI: 10.3390/ph15111321
Abstract

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

HDAC6; NKTCL; combination treatment; small molecule inhibitor; synergy.

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