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Published on: August 10, 2017
Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma
Nabanita Nawar1,2, Shazreh Bukhari1,2, Ashley A Adile3
1Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
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.
Insights
A new drug, NN-390, selectively targets HDAC6 (histone deacetylase 6) to treat aggressive pediatric brain tumors called medulloblastoma. This HDAC6 inhibitor shows promise in targeting cancer stem cells with a good safety margin.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase 6 (HDAC6) plays a role in cancer development and spread.
- Targeting HDAC6 is a strategy explored for anticancer therapies.
- Group 3 medulloblastoma (MB) is an aggressive pediatric brain tumor with poor outcomes, often linked to therapy resistance and metastasis.
Purpose of the Study:
- To design and evaluate NN-390, a novel, selective HDAC6 inhibitor.
- To assess the therapeutic potential of NN-390 against Group 3 medulloblastoma, particularly its stem cell population.
Main Methods:
- Structure-activity relationship (SAR) study to develop NN-390.
- In vitro assays to determine HDAC6 potency and selectivity against other HDAC isoforms.
- Evaluation of NN-390's efficacy in cancer cell lines and patient-derived Group 3 MB cells.
- Assessment of therapeutic margin by comparing efficacy in cancer cells versus healthy neural stem cells.
Main Results:
- NN-390 exhibits nanomolar potency against HDAC6 with high selectivity (>200-550 fold) over other HDACs.
- NN-390 demonstrates potent intracellular target engagement and cellular efficacy in cancer cell lines.
- NN-390 is the first HDAC6-selective inhibitor to show therapeutic potential in metastatic Group 3 MB.
- NN-390 selectively targets MB stem cells with a 44.3-fold therapeutic margin compared to healthy neural stem cells.
- NN-390 is 45-fold more potent than the clinical candidate citarinostat.
Conclusions:
- HDAC6-selective inhibition, exemplified by NN-390, shows significant in vitro therapeutic potential against Group 3 medulloblastoma.
- NN-390 represents a promising therapeutic strategy for aggressive pediatric brain tumors by targeting cancer stem cells.
