Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties

Krieger, Viktoria; Hamacher, Alexandra; Cao, Fangyuan; Stenzel, Katharina; Gertzen, Christoph G. W.; Schäker-Hübner, Linda; Kurz, Thomas; Gohlke, Holger; Kassack, Matthias U.; Hansen, Finn K.

doi:10.1021/acs.jmedchem.9b01489

Cited by 38 publications

(52 citation statements)

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“…Chemical structures of the HDACi tested are summarized in Supplementary Figure S1. HDAC inhibitory activity of the compounds was confirmed by analyses of hyperacetylation of histones as concluded from enzyme assays and cellular HDAC pan assays [20,30,33,79,82].…”

Section: Methodsmentioning

confidence: 86%

“…Synthesis and biological activities of the HDAC inhibitory compounds KSK64 [30] and DDK137 [79] were already described. More detailed information regarding the synthesis of the various HDACi is also provided by Pflieger et al [80], Mackwitz et al [81], and Krieger et al [82]. Chemical structures of the HDACi tested are summarized in Supplementary Figure S1.…”

Section: Methodsmentioning

confidence: 99%

“…Chemical synthesis of HDACi has already been described in detail [30,[79][80][81][82]. Chemicals and solvents were purchased from commercial suppliers (Sigma-Aldrich, (Taufkirchen, Germany); Acros Organics (Schwerte, Germany); TCI chemicals (Eschborn, Germany); Fluorochem ABCR (Karlsruhe, Germany); Alfa Aesar (Kandel, Germany); J&K chemicals (Altdorf, Germany); Carbolution (Saarbrücken, Germany)) and used without further purification.…”

Section: Chemical Synthesis Of Hdaci-reaction Monitoring Purificatimentioning

confidence: 99%

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In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

Friedrich

Assmann

Schumacher

et al. 2020

IJMS

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Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e., KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies.

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Section: Methodsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Chemical Synthesis Of Hdaci-reaction Monitoring Purificatimentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

Friedrich

Assmann

Schumacher

et al. 2020

IJMS

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“…Among these pharmacophores, Abbreviations: Cap, capping group; CD, catalytic domain; CU, connect unit; GBM, Glioblastoma; HATs, histone acetyltransferases; HDAC6, Histone deacetylase 6; HDACi, HDAC inhibitors; MD, Molecular Dynamics; MM/GBSA, Molecular Mechanics Generalized Born Surface Area; sHDAC6Is, selectivity of HDAC6 inhibitors; ZBG, zinc binding group the ZBG should penetrate deep into the bottom of the active pocket and chelate with zinc ion located in the catalytic center to compete with the protein for zinc ion, thereby inhibiting the catalytic activities of HDACs. And such binding pattern in the active pocket is the active conformation of the HDAC inhibitors (Krieger et al, 2019;Shen et al, 2019;Vergani et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics

Wang

Ren

et al. 2020

Front. Mol. Biosci.

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Glioblastoma (GBM) is the most common and aggressive intracranial malignant brain tumor, and the abnormal expression of HDAC1 is closely correlated to the progression, recurrence and metastasis of GBM cells, making selective inhibition of HDAC1 a promising strategy for GBM treatments. Among all available selective HDAC1 inhibitors, the macrocyclic peptides have gained great attention due to their remarkable inhibitory selectivity on HDAC1. However, the binding mechanism underlying this selectivity is still elusive, which increases the difficulty of designing and synthesizing the macrocyclic peptide-based anti-GBM drug. Herein, multiple computational approaches were employed to explore the binding behaviors of a typical macrocyclic peptide FK228 in both HDAC1 and HDAC6. Starting from the docking conformations of FK228 in the binding pockets of HDAC1&6, relatively long MD simulation (500 ns) shown that the hydrophobic interaction and hydrogen bonding of E91 and D92 in the Loop2 of HDAC1 with the Cap had a certain traction effect on FK228, and the sub-pocket formed by Loop1 and Loop2 in HDAC1 could better accommodate the Cap group, which had a positive effect on maintaining the active conformation of FK228. While the weakening of the interactions between FK228 and the residues in the Loop2 of HDAC6 during the MD simulation led to the large deflection of FK228 in the binding site, which also resulted in the decrease in the interactions between the Linker region of FK228 and the previously identified key amino acids (H134, F143, H174, and F203). Therefore, the residues located in Loop1 and Loop2 contributed in maintaining the active conformation of FK228, which would provide valuable hints for the discovery and design of novel macrocyclic polypeptide HDAC inhibitors.

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“…[2,3] Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are key enzymes controlling the acetylation level of histones and non-histone proteins. [4] Due to their repressive effect on gene transcription and their essential influence on drug resistance mechanisms of tumor cells, [5][6][7] HDACs are validated drug targets in epigenetic cancer therapy with four inhibitors already approved by the FDA. [8] Typically common HDAC inhibitors (HDACi) comprise a cap group, a linker region and a zinc binding group (ZBG), which is crucial for the chelation of the zinc ion inside the active site tunnel (Figure 1).…”

mentioning

confidence: 99%

Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)

et al. 2020

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Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases.

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Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties

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Cited by 38 publications

References 58 publications

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics

Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)

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