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
  • 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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