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

Harsimran Kaur Garcha; Nabanita Nawar; Helena Sorger; Fettah Erdogan; Myint Myat Khine Aung; Abootaleb Sedighi; Pimyupa Manaswiyoungkul; Hyuk-Soo Seo; Susann Schönefeldt; Daniel Pölöske; Sirano Dhe-Paganon; Heidi A Neubauer; Satu M Mustjoki; Marco Herling; Elvin D de Araujo; Richard Moriggl; Patrick T Gunning

doi:10.3390/ph15111321

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.

Authors

Harsimran Kaur Garcha^{1

2}, Nabanita Nawar^{1

2}, Helena Sorger³, Fettah Erdogan^{1

2}, Myint Myat Khine Aung³, Abootaleb Sedighi¹, Pimyupa Manaswiyoungkul^{1

2}, Hyuk-Soo Seo^{4

5}, Susann Schönefeldt³, Daniel Pölöske³, Sirano Dhe-Paganon^{4

5}, Heidi A Neubauer³, Satu M Mustjoki^{6

7

8}, Marco Herling⁹, Elvin D de Araujo¹, Richard Moriggl³, 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.

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.

Abstract

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