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

Darwish, Salma; Ghazy, Ehab; Heimburg, Tino; Herp, Daniel; Zeyen, Patrik; Salem-Altintas, Rabia; Ridinger, Johannes; Robaa, Dina; Schmidtkunz, Karin; Erdmann, Frank; Romier, Christophe; Jung, Manfred; Oehme, Ina; Sippl, Wolfgang

doi:10.3390/ijms23147535

Cited by 23 publications

(20 citation statements)

References 71 publications

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“…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. Interestingly, a chemoproteomics study by Xiong et al demonstrated that HDAC6 and HDAC3 are most amenable for targeted protein degradation.…”

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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“…Investigation of the potential anti-neuroblastoma activity of newly designed HDAC8 degraders was pursued by Darwish et al [ 189 ], due to the critical involvement of HDAC8 in this pathology. The developed PROTACs were designed starting from previously disclosed benzhydroxamic HDAC8 inhibitors [ 143 , 189 ]. Different E3 ligase ligands, including CRBN and VHL, were explored to evaluate how the target degradation would be affected.…”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

“…PROTAC 74 also showed strong hyperacetylation of SMC3, as opposed to the negative control bearing an ester in place of the hydroxamic acid motif. Treatment of neuroblastoma cells with PROTAC 74 also led to neuronal differentiation, as confirmed by neurite-like outgrowths and enhanced differentiated phenotype in microscopic analysis [ 189 ]. These results confirm the potential therapeutic application of HDAC8-degrading PROTACs in neuroblastoma and pave the way towards the future development of novel epigenetic degraders for the treatment of complex diseases.…”

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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From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Zhao

Chen

Huang

et al. 2023

Interdisciplinary Medicine

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Proteolysis-targeting chimeras (PROTACs) is a targeted protein degradation (TPD) technique effected by hijacking the ubiquitin-proteasome system (UPS) of the cells. A PROTAC molecule specifically binds to its protein of interest (POI) and recruits an E3 ligase to assemble a ternary complex. The POI was subsequently ubiquitinated, followed by being degraded by proteasomes. After 20 years of development, PROTAC technology has made a significant progress, and quite some candidates have entered clinical trials. Along with the excitement of realizing that PROTAC technology can develop therapeutics toward those traditionally believed "undruggable" targets; there are still unmet demands in PROTAC design, screening, and intracellular availability. PROTAC technology is rapidly advancing from employing traditional medicinal chemistry methodologies to integrating state-of-the-art chemical biology technologies, becoming a typical example of interdisciplinary medicine. This review summarizes the progress made in PROTAC technology in recent years, including expanding new targets, developing dual-target PROTACs, rational design and screening strategies, regulatory activation, targeted delivery, and developing biological macromolecule-contained PROTACs.

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

Cited by 23 publications

References 71 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

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

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

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