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

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.

HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer

“…Ricolinostat and Citarinostat (Figure 3) are hydroxamates, which are quite selective toward the Class-II HDAC6 (HDAC1/HDAC6 selectivity index = 13 and 12, respectively) and are under evaluation against different malignancies [15,16]. In general, new and more selective HDAC6 inhibitors have been disclosed as useful tools to counteract tumor progression [17,18], although it was also reported that the selective inhibition of HDAC6 is not necessarily related to an anticancer activity, as observed for Tubathian A (Figure 3) and related compounds [19]. Therefore, increasing attention is required for the evaluation of HDAC inhibitors as anticancer drugs, especially when used as single agents.…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…Unlike other HDACs, the development of HDAC6-specific inhibitors has been relatively successful [ 6 , 7 , 47 ]. NN-390, the first HDAC6-selective inhibitor, has shown therapeutic potential for Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor associated with leptomeningeal metastases and therapy resistance [ 48 ]. NM-390 targets MB stem cells and demonstrates a 45-fold increased efficacy over HDAC6 inhibitor citarinostat (ACY-241) [ 48 ].…”

“…NN-390, the first HDAC6-selective inhibitor, has shown therapeutic potential for Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor associated with leptomeningeal metastases and therapy resistance [ 48 ]. NM-390 targets MB stem cells and demonstrates a 45-fold increased efficacy over HDAC6 inhibitor citarinostat (ACY-241) [ 48 ]. ACY-1215 was shown to inhibit the translocation of GRP78 to the plasma membrane by inhibiting the PI3K/AKT signaling [ 47 ].…”

High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma

“…The synthetic pathway used to furnish NN-429 is outlined in Scheme 1. Synthesis of NN-390 has been previously described [27]. Tert-butyl ester protection of 3-fluoro-4-methylbenzoic acid (1) led to the generation of tert-butyl 3-fluoro-4-methylbenzoate (2, 70%), which was then brominated at the benzylic position (3, 56%).…”

“…Given these clinical needs, particularly for the incurable, aggressive, and rare entities of γδ T-NHL and NKTCLs, we aimed to design an HDAC6 inhibitor with drug-like properties, explored here via medicinal chemistry, X-ray crystallography studies, pharmacological and biochemical methodologies. NN-429 is an improved analog of older generation HDAC6 inhibitor molecules KT-531 and NN-390, with higher in vitro selectivity, target potency and in vivo half-life [10,27]. We specifically studied our novel HDAC6 inhibitor, NN-429, in a panel of human PTCL cell lines to explore targeted drug efficacy, finding the highest sensitives in hepatosplenic γδ T-NHL and NKTCL derived cell lines.…”