High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma
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, inc...
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| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/11/1321 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Harsimran Kaur Garcha |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T18:45:09Z |
| format | Article |
| id | doaj.art-87a893d2ff80432881eea8c588541e56 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T18:45:09Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-87a893d2ff80432881eea8c588541e562023-11-24T06:18:03ZengMDPI AGPharmaceuticals1424-82472022-10-011511132110.3390/ph15111321High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell LymphomaHarsimran Kaur Garcha0Nabanita Nawar1Helena Sorger2Fettah Erdogan3Myint Myat Khine Aung4Abootaleb Sedighi5Pimyupa Manaswiyoungkul6Hyuk-Soo Seo7Susann Schönefeldt8Daniel Pölöske9Sirano Dhe-Paganon10Heidi A. Neubauer11Satu M. Mustjoki12Marco Herling13Elvin D. de Araujo14Richard Moriggl15Patrick T. Gunning16Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USAInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USAInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaTranslational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, FinlandDepartment of Hematology, Cellular Therapy, and Hemostaseology, University of Leipzig, 04109 Leipzig, GermanyDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, CanadaNK/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.https://www.mdpi.com/1424-8247/15/11/1321NKTCLHDAC6synergycombination treatmentsmall molecule inhibitor |
| spellingShingle | 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 High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma Pharmaceuticals NKTCL HDAC6 synergy combination treatment small molecule inhibitor |
| title | High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma |
| title_full | High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma |
| title_fullStr | High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma |
| title_full_unstemmed | High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma |
| title_short | High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma |
| title_sort | high efficacy and drug synergy of hdac6 selective inhibitor nn 429 in natural killer nk t cell lymphoma |
| topic | NKTCL HDAC6 synergy combination treatment small molecule inhibitor |
| url | https://www.mdpi.com/1424-8247/15/11/1321 |
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