Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma Academic Article uri icon

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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.

authors

  • 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
  • Gunning, Patrick T

publication date

  • February 24, 2022

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