TY - JOUR
T1 - Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma
AU - Nawar, Nabanita
AU - Bukhari, Shazreh
AU - Adile, Ashley A.
AU - Suk, Yujin
AU - Manaswiyoungkul, Pimyupa
AU - Toutah, Krimo
AU - Olaoye, Olasunkanmi O.
AU - Raouf, Yasir S.
AU - Sedighi, Abootaleb
AU - Garcha, Harsimran Kaur
AU - Hassan, Muhammad Murtaza
AU - Gwynne, William
AU - Israelian, Johan
AU - Radu, Tudor B.
AU - Geletu, Mulu
AU - Abdeldayem, Ayah
AU - Gawel, Justyna M.
AU - Cabral, Aaron D.
AU - Venugopal, Chitra
AU - De Araujo, Elvin D.
AU - Singh, Sheila K.
AU - Gunning, Patrick T.
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/2/24
Y1 - 2022/2/24
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c01585
DO - 10.1021/acs.jmedchem.1c01585
M3 - Article
C2 - 35119267
AN - SCOPUS:85124467698
SN - 0022-2623
VL - 65
SP - 3193
EP - 3217
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -
