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

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.

Citation

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 Araujo, Sheila K Singh, Patrick T Gunning. Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma. Journal of medicinal chemistry. 2022 Feb 24;65(4):3193-3217

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PMID: 35119267

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