Development of the first non-hydroxamate selective HDAC6 degraders

Keuler, Tim; König, Beate; Bückreiß, Nico; Kraft, Fabian B.; König, Philipp; Schäker-Hübner, Linda; Steinebach, Christian; Bendas, Gerd; Gütschow, Michael; Hansen, Finn K.

doi:10.1039/d2cc03712b

Cited by 28 publications

(31 citation statements)

References 17 publications

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“…[30][31][32][33]35 These findings raise the intriguing question, whether a selective or unselective HDAC6 ligand is superior to develop highly efficient and selective HDAC6 degraders. Even though most work on HDAC PROTACs has focused on HDAC6, 38 the first degraders of HDAC1, HDAC2, and/or HDAC3 utilizing a hydrazide or aminoanilide zincbinding group were recently disclosed. 24,28,36,37 Furthermore, in 2022, the first selective HDAC4 39 and HDAC8 27,29,40 PROTACs were reported.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Subsequently, additional selective HDAC6 degraders were discovered based on the selective HDAC6i nexturastat A. − , These findings raise the intriguing question, whether a selective or unselective HDAC6 ligand is superior to develop highly efficient and selective HDAC6 degraders. Even though most work on HDAC PROTACs has focused on HDAC6, the first degraders of HDAC1, HDAC2, and/or HDAC3 utilizing a hydrazide or aminoanilide zinc-binding group were recently disclosed. ,,, Furthermore, in 2022, the first selective HDAC4 and HDAC8 ,, PROTACs were reported. Interestingly, a chemoproteomics study by Xiong et al demonstrated that HDAC6 and HDAC3 are most amenable for targeted protein degradation …”

Section: Introductionmentioning

confidence: 99%

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Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

et al. 2022

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In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of histone deacetylase 6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin–proteasome pathway, with DC50 values of 3.5 and 19.4 nM, respectively. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

et al. 2022

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“…1 Our previous work has been devoted to mechanistic investigations of anti-myeloma agents such as the immunomodulatory drugs (IMiDs) pomalidomide and lenalidomide (Figure 1), [7][8][9] as well as medicinal chemistry in the field of targeted protein degradation with particular focus on PROTACs that hijack the E3 ligase cereblon (CRBN). [10][11][12][13][14][15] Recently, a new class of CRBN ligands has been coined, i.e. CRBN E3 ligase modulators (CELMoDs), which are typically based on aminoglutarimide as the core binding moiety, [17][18][19][20][21] and to which examples such as iberdomide (CC-220, Figure 1) and mezigdomide (CC-92480) belong.…”

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Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

et al. 2023

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“…The work of Keuler, König, Bückreiß, and colleagues [ 85 ] reports the development of compounds with a difluoromethyl-1,3,4-oxadiazole scaffold that serves to bind zinc instead of a hydroxamate ( Figure 11 ). These non-hydroxamate compounds were found to function as proteolysis-targeting chimeras (PROTACs) for the intended degradation of a specific protein, e.g., HDAC.…”

Section: Biological Significance and Purpose Of Fluorination In Hdacismentioning

confidence: 99%

“… Chemical structures of fluorinated HDAC6-addressing PROTACs by Keuler, König, Bückreiß et al [ 85 ]. …”

Section: Figures and Schemesmentioning

confidence: 99%

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

et al. 2023

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In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal–chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomo-graphy of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

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Development of the first non-hydroxamate selective HDAC6 degraders

Abstract: The targeted degradation of histone deacetylase 6 (HDAC6) by heterobifunctional degraders constitutes a promising approach to treat HDAC6-driven diseases. Previous HDAC6 selective degraders utilised a hydroxamic acid as a zinc-binding...

Cited by 28 publications

References 17 publications

Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

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