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Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma.
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; Gunning, Patrick T.
Afiliación
  • Nawar N; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Bukhari S; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Adile AA; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Suk Y; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Manaswiyoungkul P; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
  • Toutah K; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
  • Olaoye OO; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Raouf YS; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Sedighi A; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Garcha HK; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Hassan MM; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Gwynne W; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Israelian J; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Radu TB; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Geletu M; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Abdeldayem A; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Gawel JM; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Cabral AD; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Venugopal C; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
  • de Araujo ED; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • Singh SK; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • Gunning PT; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
J Med Chem ; 65(4): 3193-3217, 2022 02 24.
Article en En | MEDLINE | ID: mdl-35119267
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-390 is 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-390 is 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-390 selectively 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-390 demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitro therapeutic potential against Group 3 MB.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Inhibidores de Histona Desacetilasas / Histona Desacetilasa 6 / Meduloblastoma / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Canadá
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Inhibidores de Histona Desacetilasas / Histona Desacetilasa 6 / Meduloblastoma / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Canadá