Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma

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

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3193-3217
Number of pages25
JournalJournal of Medicinal Chemistry
Volume65
Issue number4
DOIs
Publication statusPublished - Feb 24 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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