Identification of histone deacetylase 10 (HDAC10) inhibitors that modulate autophagy in transformed cells

Zeyen, Patrik; Zeyn, Yanira; Herp, Daniel; Mahmoudi, Fereshteh; Yesiloglu, Talha Z.; Erdmann, Frank; Schmidt, Matthias; Robaa, Dina; Romier, Christophe; Ridinger, Johannes; Herbst-Gervasoni, C.J.; Christianson, D.W.; Oehme, Ina; Jung, Manfred; Krämer, Oliver; Sippl, Wolfgang

doi:10.1016/j.ejmech.2022.114272

Cited by 19 publications

(26 citation statements)

References 47 publications

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“…The Zn 2+ ligand H176 donates a hydrogen bond to E274 as well, as also observed in the HDAC10–tubastatin A complex, thereby forming a hydrogen bond network between H176 and the anilide NH group. Water-mediated hydrogen bond networks with H176 are also observed in other HDAC10–inhibitor complexes. ,, …”

Section: Resultsmentioning

confidence: 86%

“…Watermediated hydrogen bond networks with H176 are also observed in other HDAC10−inhibitor complexes. 10,11,41 The 2.15 Å resolution crystal structure of the HDAC10−14 complex (Figure 4B) reveals that the tertiary amine installed at the δ-position of the inhibitor, which is protonated and hence positively charged at physiological pH, makes a weak cation−π interaction with W205 and a long-range electrostatic interaction with gatekeeper residue E274 (the N---O separation of 4.2 Å is too long for hydrogen bonding). As in the SAHA and tubastatin A structures, E274 forms a hydrogen bond with H176.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The Class IIB enzymes are distinct from the Class I isozymes (HDACs 1, 2, 3, 8) in that they exhibit poor deacetylase activity on histones and localize primarily in the cytoplasm. Despite decades of intense research on the HDAC family, HDAC10 has received comparatively little attention by the medicinal chemistry community, − resulting in a lack of appropriate pharmacological tools. Indeed, it took 15 years after its isolation before HDAC10 was shown to be a poor lysine deacetylase, which instead recognizes acetylated polyamines as substrates.…”

Section: Introductionmentioning

confidence: 99%

“…Up to now, no HDAC10i that fulfills the requirements of a selective chemical probe has been described . While HDAC10 inhibitors with selectivity over the Class I isozymes are known, the primary challenge lies in achieving selectivity over the other Class IIB member, HDAC6. ,− A good example for this is tubastatin A ( 1 ), a well-known HDAC6i, which is an even more potent HDAC10 binder (Figure , far left box). , We previously showed that an electrostatic interaction between the tertiary amine of the tetrahydro-γ-carboline ring of 1 and the E274 gatekeeper residue in HDAC10 is responsible for its strong binding. , The gatekeeper residue is unique to HDAC10, and its negative charge provides an attractive interaction with positively charged polyamines (or HDAC10 inhibitors) within HDAC10’s binding site. Ring-opened tubastatin A derivative DKFZ‑480 ( 2 ) makes a direct hydrogen bond to E274, which results in enhanced binding affinity.…”

Section: Introductionmentioning

confidence: 99%

“…Linear, diamine PDAC inhibitors like 10 have been known for decades, 15,17,33 and some have recently been crystallized with HDAC10. 34 We hypothesized that merging SAHA (9) and diamine PDAC inhibitors like 10 into aza-SAHA derivatives (11) would render the SAHA linker into a motif only recognized by HDAC10, effectively converting SAHA from a pan-inhibitor into an HDAC10-selective chemical probe. These compounds, containing both an amino group and a hydroxamic acid, would be highly polar, but the anilide cap group would render them more drug-like than 10 and offer a synthetic handle (R 2 ) for…”

Section: ■ Introductionmentioning

confidence: 99%

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Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

et al. 2022

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We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one-atom replacement (C→N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with potency and selectivity demonstrated by cellular and biochemical target engagement, as well as thermal shift assays. Cocrystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling confirmed exquisite cellular HDAC10-selectivity of DKFZ‑748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ‑748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.

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Section: Resultsmentioning

confidence: 86%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

et al. 2022

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Novel (E)‐3‐(3‐Oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation

Sang

Anh

et al. 2023

Chemistry & Biodiversity

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Herein, we report the design, synthesis and evaluation of novel (E)-3- (3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6yl)-N-hydroxypropenamides (4 a-i, 7 a-g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCIÀ H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a-i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a-g in all biological assays. Compounds 7 e-f were found to be the most active HDAC inhibitors with IC 50 of 1.498 � 0.020 μM and 1.794 � 0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC 50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.

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First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Selective Inhibitors with Cellular Target Engagement**

et al. 2022

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Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e. g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of most other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to meas-ure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was [**] A previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.26434/chemrxiv-2022-pqhtn-v4).

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Identification of histone deacetylase 10 (HDAC10) inhibitors that modulate autophagy in transformed cells

Cited by 19 publications

References 47 publications

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

Novel (E)‐3‐(3‐Oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Selective Inhibitors with Cellular Target Engagement**

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