Selective degradation of histone deacetylase 8 mediated by a proteolysis targeting chimera (PROTAC)

Chotitumnavee, Jiranan; Yamashita, Yasunobu; Takahashi, Yukari; Takada, Yuri; Iida, Tetsuya; Oba, Makoto; Itoh, Yukihiro; Suzuki, Takayoshi

doi:10.1039/d2cc00272h

Cited by 28 publications

(18 citation statements)

References 45 publications

(21 reference statements)

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“…A para -substituted analogue, which proved to be inactive, was also synthesized to confirm that the meta position was the most favourable to obtain HDAC8 degradation. [ 187 ].…”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

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A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Fontana

Cursaro

Carullo

et al. 2022

IJMS

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Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.

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“…A para -substituted analogue, which proved to be inactive, was also synthesized to confirm that the meta position was the most favourable to obtain HDAC8 degradation. [ 187 ].…”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

“… Representation of reported HDAC8-degraders and HDAC8-inhibiting precursors [ 142 , 143 , 160 , 187 , 188 , 189 ]. …”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Fontana

Cursaro

Carullo

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…Recently, Chotitumnavee et al [ 49 ] reported the development of an HDAC8 PROTAC. In the three synthesized degraders, a reported NCC-149 analogue [ 11 ] was used as POI ligand and pomalidomide was used as the E3 ubiquitin ligase ligand.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Darwish

Ghazy

Heimburg

et al. 2022

IJMS

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In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in several studies, HDAC8 can be considered a potential target in the treatment of cancer forms such as childhood neuroblastoma. The present work describes the development of proteolysis targeting chimeras (PROTACs) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we investigated the HDAC8-degrading profiles of the synthesized PROTACs and their effect on the proliferation of neuroblastoma cells. The combination of in vitro screening and cellular testing demonstrated selective HDAC8 PROTACs that show anti-neuroblastoma activity in cells.

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“…20 The development of HDAC degraders is of emerging interest and a few HDAC degraders were disclosed in recent years. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] In 2017, Schiedel et al described the first degraders of sirtuin 2 (Sirt2). 22 The first degraders of a Zn 2+ -dependent HDAC were reported in 2018 by Yang et al by utilizing pomalidomide as a recruiter for the E3 ligase cereblon (CRBN) and the unselective HDACi crebinostat as POI ligand.…”

Section: Introductionmentioning

confidence: 99%

“…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 zinc-binding group were recently disclosed. 24,28,36,37 Furthermore, in 2022, the first selective HDAC4 39 and HDAC8 27,29,40 PROTACs were reported. Interestingly, a chemo-proteomics study by Xiong et al demonstrated that HDAC6 and HDAC3 are most amenable for targeted protein degradation.…”

Section: Introductionmentioning

confidence: 99%

Solid-phase synthesis of cereblon-recruiting selective histone deacetylase 6 degraders (HDAC6 PROTACs) with anti-leukemic activity

Sinatra

Yang

Schliehe‐Diecks

et al. 2022

Preprint

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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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Selective degradation of histone deacetylase 8 mediated by a proteolysis targeting chimera (PROTAC)

Abstract: We developed a first-in-class proteolysis targeting chimera (PROTAC) for selective degradation of histone deacetylase 8 (HDAC8). The PROTAC induced degradation of HDAC8 without affecting the levels of other HDACs in...

Cited by 28 publications

References 45 publications

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Solid-phase synthesis of cereblon-recruiting selective histone deacetylase 6 degraders (HDAC6 PROTACs) with anti-leukemic activity

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