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

  • J Med Chem. 2022 Feb 24;65(4):3193-3217. doi: 10.1021/acs.jmedchem.1c01585.
Nabanita Nawar  1  2 ,  Shazreh Bukhari  1  2 ,  Ashley A Adile  3 ,  Yujin Suk  3 ,  Pimyupa Manaswiyoungkul  1  2 ,  Krimo Toutah  1 ,  Olasunkanmi O Olaoye  1  2 ,  Yasir S Raouf  1  2 ,  Abootaleb Sedighi  1 ,  Harsimran Kaur Garcha  1  2 ,  Muhammad Murtaza Hassan  1  2 ,  William Gwynne  3 ,  Johan Israelian  1  2 ,  Tudor B Radu  1  2 ,  Mulu Geletu  1 ,  Ayah Abdeldayem  1  2 ,  Justyna M Gawel  1 ,  Aaron D Cabral  1  2 ,  Chitra Venugopal  3  4 ,  Elvin D de Araujo  1 ,  Sheila K Singh  3  4 ,  Patrick T Gunning  1  2
Affiliations
  • 1. Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • 2. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • 3. Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
  • 4. Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
PMID: 35119267 DOI: 10.1021/acs.jmedchem.1c01585
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143877
    NN-390
    HDAC6 Inhibitor
    target: HDAC
    Research Areas: Cancer