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14 results on '"Nawar, Nabanita"'

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

Author

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

Subjects
Drug Discovery, Pharmaceutical Science, Molecular Medicine, T-Cell Lymphoma, Histone Deacetylase Inhibitor, Refinement, Therapy, Tubulin, Cancer, Hdac6, Features, Assay, NKTCL, HDAC6, synergy, combination treatment, small molecule inhibitor
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.

Published
2022
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5. Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma

Author

Nawar, Nabanita, primary, Bukhari, Shazreh, additional, Adile, Ashley A., additional, Suk, Yujin, additional, Manaswiyoungkul, Pimyupa, additional, Toutah, Krimo, additional, Olaoye, Olasunkanmi O., additional, Raouf, Yasir S., additional, Sedighi, Abootaleb, additional, Garcha, Harsimran Kaur, additional, Hassan, Muhammad Murtaza, additional, Gwynne, William, additional, Israelian, Johan, additional, Radu, Tudor B., additional, Geletu, Mulu, additional, Abdeldayem, Ayah, additional, Gawel, Justyna M., additional, Cabral, Aaron D., additional, Venugopal, Chitra, additional, de Araujo, Elvin D., additional, Singh, Sheila K., additional, and Gunning, Patrick T., additional

Published
2022
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6. Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Author

Toutah, Krimo, Nawar, Nabanita, Timonen, Sanna, Sorger, Helena, Raouf, Yasir S., Bukhari, Shazreh, von Jan, Jana, Ianevski, Aleksandr, Gawel, Justyna M., Olaoye, Olasunkanmi O., Geletu, Mulu, Abdeldayem, Ayah, Israelian, Johan, Radu, Tudor B., Sedighi, Abootaleb, Bhatti, Muzaffar N., Hassan, Muhammad Murtaza, Manaswiyoungkul, Pimyupa, Shouksmith, Andrew E., Neubauer, Heidi A., de Araujo, Elvin D., Aittokallio, Tero, Kraemer, Oliver H., Moriggl, Richard, Mustjoki, Satu, Herling, Marco, Gunning, Patrick T., Toutah, Krimo, Nawar, Nabanita, Timonen, Sanna, Sorger, Helena, Raouf, Yasir S., Bukhari, Shazreh, von Jan, Jana, Ianevski, Aleksandr, Gawel, Justyna M., Olaoye, Olasunkanmi O., Geletu, Mulu, Abdeldayem, Ayah, Israelian, Johan, Radu, Tudor B., Sedighi, Abootaleb, Bhatti, Muzaffar N., Hassan, Muhammad Murtaza, Manaswiyoungkul, Pimyupa, Shouksmith, Andrew E., Neubauer, Heidi A., de Araujo, Elvin D., Aittokallio, Tero, Kraemer, Oliver H., Moriggl, Richard, Mustjoki, Satu, Herling, Marco, and Gunning, Patrick T.

Abstract

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as standalone or in combination with targeted drugs.

Published
2021

7. Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Author

Toutah, Krimo, primary, Nawar, Nabanita, additional, Timonen, Sanna, additional, Sorger, Helena, additional, Raouf, Yasir S., additional, Bukhari, Shazreh, additional, von Jan, Jana, additional, Ianevski, Aleksandr, additional, Gawel, Justyna M., additional, Olaoye, Olasunkanmi O., additional, Geletu, Mulu, additional, Abdeldayem, Ayah, additional, Israelian, Johan, additional, Radu, Tudor B., additional, Sedighi, Abootaleb, additional, Bhatti, Muzaffar N., additional, Hassan, Muhammad Murtaza, additional, Manaswiyoungkul, Pimyupa, additional, Shouksmith, Andrew E., additional, Neubauer, Heidi A., additional, de Araujo, Elvin D., additional, Aittokallio, Tero, additional, Krämer, Oliver H., additional, Moriggl, Richard, additional, Mustjoki, Satu, additional, Herling, Marco, additional, and Gunning, Patrick T., additional

Published
2021
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8. Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype

Author

Olaoye, Olasunkanmi O., primary, Watson, Paris R., additional, Nawar, Nabanita, additional, Geletu, Mulu, additional, Sedighi, Abootaleb, additional, Bukhari, Shazreh, additional, Raouf, Yasir S., additional, Manaswiyoungkul, Pimyupa, additional, Erdogan, Fettah, additional, Abdeldayem, Ayah, additional, Cabral, Aaron D., additional, Hassan, Muhammad Murtaza, additional, Toutah, Krimo, additional, Shouksmith, Andrew E., additional, Gawel, Justyna M., additional, Israelian, Johan, additional, Radu, Tudor B., additional, Kachhiyapatel, Niyati, additional, de Araujo, Elvin D., additional, Christianson, David W., additional, and Gunning, Patrick T., additional

Published
2021
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9. Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting

Author

Hassan, Muhammad Murtaza, primary, Israelian, Johan, additional, Nawar, Nabanita, additional, Ganda, Giovanni, additional, Manaswiyoungkul, Pimyupa, additional, Raouf, Yasir S., additional, Armstrong, David, additional, Sedighi, Abootaleb, additional, Olaoye, Olasunkanmi O., additional, Erdogan, Fettah, additional, Cabral, Aaron D., additional, Angeles, Fabrizio, additional, Altintas, Rabia, additional, de Araujo, Elvin D., additional, and Gunning, Patrick T., additional

Published
2020
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10. Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

Author

Shouksmith, Andrew E., primary, Gawel, Justyna M., additional, Nawar, Nabanita, additional, Sina, Diana, additional, Raouf, Yasir S., additional, Bukhari, Shazreh, additional, He, Liying, additional, Johns, Alexandra E., additional, Manaswiyoungkul, Pimyupa, additional, Olaoye, Olasunkanmi O., additional, Cabral, Aaron D., additional, Sedighi, Abootaleb, additional, de Araujo, Elvin D., additional, and Gunning, Patrick T., additional

Published
2019
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13. Discovery of HDAC6-Selective Inhibitor NN-390 with in VitroEfficacy in Group 3 Medulloblastoma

Author

Nawar, Nabanita, Bukhari, Shazreh, Adile, Ashley A., Suk, Yujin, Manaswiyoungkul, Pimyupa, Toutah, Krimo, Olaoye, Olasunkanmi O., Raouf, Yasir S., Sedighi, Abootaleb, Garcha, Harsimran Kaur, Hassan, Muhammad Murtaza, Gwynne, William, Israelian, Johan, Radu, Tudor B., Geletu, Mulu, Abdeldayem, Ayah, Gawel, Justyna M., Cabral, Aaron D., Venugopal, Chitra, de Araujo, Elvin D., Singh, Sheila K., and Gunning, Patrick T.

Abstract

Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role in oncogenic transformation and metastasis. Through a second-generation structure–activity relationship (SAR) study, the design, and biological evaluation of the selective HDAC6 inhibitor NN-390is reported. With nanomolar HDAC6 potency, >200–550-fold selectivity for HDAC6 in analogous HDAC isoform functional assays, potent intracellular target engagement, and robust cellular efficacy in cancer cell lines, NN-390is the first HDAC6-selective inhibitor to show therapeutic potential in metastatic Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor often associated with leptomeningeal metastases and therapy resistance. MB stem cells contribute to these patients’ poor clinical outcomes. NN-390selectively targets this cell population with a 44.3-fold therapeutic margin between patient-derived Group 3 MB cells in comparison to healthy neural stem cells. NN-390demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitrotherapeutic potential against Group 3 MB.

Published
2022
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14. Evaluation of Small-Molecule HDAC Inhibitors Through In Vitro and In Cellulo Approaches.

Author

Nawar N, Garcha HK, Sedighi A, de Araujo ED, and Gunning PT

Subjects
Protein Isoforms metabolism, Membranes, Artificial, Lipids, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors chemistry, Histone Deacetylases metabolism
Abstract

The aberrant activity of histone deacetylases (HDACs) across a broad range of cancers and other disease indications has led to the development of small-molecule inhibitors that target one or more members of the HDAC protein family. Emerging HDAC inhibitors that show promise in drug discovery programs must be assessed across a range of in vitro assays to establish an inhibitor profile for potency and cellular selectivity towards target HDAC(s) as well as preliminary absorption, distribution, metabolism, and excretion (ADME) features. Here we provide an overview of methods to determine a subset of pivotal in vitro drug-like parameters for HDAC inhibitors (HDACi). We initially describe protocols for parallel artificial membrane permeability assays (PAMPA) to evaluate the passive permeability of small molecules across lipid membranes. Subsequently, we elaborate on cytotoxicity assays using CellTiter-Blue to determine HDACi-induced cell death in healthy/diseased cellular models. We next focus on assessing the target engagement of inhibitors with the appropriate HDAC isoforms in a cellular environment via Western blotting of acetylated HDAC substrates. Finally, we provide detailed guidelines on how to assess the metabolic stability of HDACi through whole blood stability assays. Collectively, these assays provide an overview of the permeability, selectivity, and stability of the HDAC inhibitor under development., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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