Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

Heimburg, Tino; Kolbinger, Fiona R.; Zeyen, Patrik; Ghazy, Ehab; Herp, Daniel; Schmidtkunz, Karin; Melesina, Jelena; Shaik, T.B.; Erdmann, Frank; Schmidt, Matthias; Romier, Christophe; Robaa, Dina; Witt, Olaf; Oehme, Ina; Jung, Manfred; Sippl, Wolfgang

doi:10.1021/acs.jmedchem.7b01447

Cited by 67 publications

(79 citation statements)

References 65 publications

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“…WY‐15 also displayed pan‐HDACs inhibitory activity with slight selectivity to HDAC6 and 8. Published studies demonstrated that HDAC6 and HDAC8 inhibitors can potently kill the MM cells (Hideshima et al, ) and neuroblastoma cells (Heimburg et al, ), respectively, so, the isoform selectivity result was consistent with the cell level results that WY‐15 exhibited potent growth inhibition activities toward NCI‐H929 (MM) and Sy5y (neuroblastoma) cells.…”

Section: Resultssupporting

confidence: 66%

Novel histone deacetylase inhibitors bearing a 4‐piperidin‐4‐yl‐triazole scaffold as antitumor agents

Wang

et al. 2019

Drug Development Research

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Histone deacetylases have proven to be promising targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of 20 novel hydroxamic acid‐based histone deacetylase inhibitors with 4‐piperidin‐4‐yl‐triazole as the core structure. Five newly obtained compounds displayed excellent HDAC6 inhibitory activities. Among them, compounds WY‐12 and WY‐15 also exhibited excellent antiproliferative activities against six human tumor cell lines. WY‐15 could increase the level of acetylated histone H3 in a dose‐dependent manner. Furthermore, WY‐15 remarkably induced cell cycle arrest of Sy5y cancer cells in G0/G1 phase. Finally, the high potency of compound WY‐15 toward HDAC6 was rationalized by molecular docking study.

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Section: Resultssupporting

confidence: 66%

Novel histone deacetylase inhibitors bearing a 4‐piperidin‐4‐yl‐triazole scaffold as antitumor agents

Wang

et al. 2019

Drug Development Research

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“…Fluorometric determination of biochemical HDAC inhibition displayed no substantial effect against HDACs 1, 3 (Supplementary Table, Supplementary Fig. 1a, (Heimburg et al 2017 )) as well as class IIa HDACs (Supplementary Table, Supplementary Fig. 1b, c).…”

Section: Resultsmentioning

confidence: 95%

“…1a, b). Following computer-based screening of an in-house library of hydroxamic acids, inhibitors displaying promising effects in cell-free biochemical assays were tested for specificity and anti-tumor effects in multiple pediatric cancer cell lines, including high-grade neuroblastoma cells (Heimburg et al 2017). Fluorometric determination of biochemical HDAC inhibition displayed no substantial effect against HDACs 1, 3 (Supplementary Table, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

et al. 2018

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High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in vivo. HDAC10 inhibition increases intracellular accumulation of chemotherapeutics through interference with lysosomal homeostasis, ultimately leading to cell death in cultured neuroblastoma cells. So far, no HDAC inhibitor covering HDAC8 and HDAC10 at micromolar concentrations without inhibiting HDACs 1, 2 and 3 has been described. Here, we introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic acid), a novel HDAC6/8/10 inhibitor for neuroblastoma therapy. TH34 is well-tolerated by non-transformed human skin fibroblasts at concentrations up to 25 µM and modestly impairs colony growth in medulloblastoma cell lines, but specifically induces caspase-dependent programmed cell death in a concentration-dependent manner in several human neuroblastoma cell lines. In addition to the induction of DNA double-strand breaks, HDAC6/8/10 inhibition also leads to mitotic aberrations and cell-cycle arrest. Neuroblastoma cells display elevated levels of neuronal differentiation markers, mirrored by formation of neurite-like outgrowths under maintained TH34 treatment. Eventually, after long-term treatment, all neuroblastoma cells undergo cell death. The combination of TH34 with plasma-achievable concentrations of retinoic acid, a drug applied in neuroblastoma therapy, synergistically inhibits colony growth (combination index (CI) < 0.1 for 10 µM of each). In summary, our study supports using selective HDAC inhibitors as targeted antineoplastic agents and underlines the therapeutic potential of selective HDAC6/8/10 inhibition in high-grade neuroblastoma.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2234-8) contains supplementary material, which is available to authorized users.

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“…The efficacy of HDAC8 inhibition, crizotinib and the combination was assessed by evaluating tumor volume change, quantified via semi-automated image analysis, from day one (start of treatment) to day three (end of experiment) post-implantation . Here, we used the novel compound 20a, a hydroxamate-based inhibitor selective for HDAC8, not targeting HDAC1–3 [ 29 ], since PCI-34051 was toxic to zebrafish embryos (Supplementary Figure 2B ). Overall, our results imply sensitizing effects of the combinatorial treatment of crizotinib with HDAC8 inhibition in SK-N-BE(2)-C cells.…”

Section: Resultsmentioning

confidence: 99%

A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment

et al. 2018

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The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3–6 µM PCI-34051 or 10 µM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 µM (ALK-amplified) to 0.8 µM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.

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Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

Cited by 67 publications

References 65 publications

Novel histone deacetylase inhibitors bearing a 4‐piperidin‐4‐yl‐triazole scaffold as antitumor agents

Novel histone deacetylase inhibitors bearing a 4‐piperidin‐4‐yl‐triazole scaffold as antitumor agents

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment

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