Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs

Xiao, Yonglong; Wang, Jia; Zhao, Lisa; Chen, Xinyi; Zheng, Guangrong; Zhang, Xuan; Liao, Daiqing

doi:10.1039/d0cc03243c

Cited by 73 publications

(68 citation statements)

References 40 publications

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“…While dHDAC6 demonstrated efficient degradation of HDAC6 in MCF-7 breast cancer cells, the multiple myeloma cell line MM.1S was more sensitive to dHDAC6 in regard to degradation of HDAC6 [278,279]. Since the initial report by Yang et al, several other HDAC degraders have been disclosed, including selective HDAC6 PROTACs [256,[279][280][281][282][283], class I-selective PRO-TACs [284][285][286] and HDAC3-selective degraders [287]. Although most work has focused on hematological cancers so far, there are some encouraging results indicating that HDAC PROTACs could be an innovative new option for the treatment of solid cancers.…”

Section: Protacsmentioning

confidence: 99%

“…By utilizing a benzoylhydrazide-based ZBG, Xiao et al reported a new type of HDAC PROTAC capable of degrading HDAC3 in a potent and selective manner [ 287 ]. The most promising PROTAC XZ9002 ( Figure 7 ) dose-dependently induced HDAC3 degradation in the triple negative breast cancer cell line MDA-MB-468, with a DC 50 value (half-degrading concentration) of 42 nM.…”

Section: Bifunctional Hdac Inhibitors For Cancer Therapymentioning

confidence: 99%

“…The most promising PROTAC XZ9002 ( Figure 7 ) dose-dependently induced HDAC3 degradation in the triple negative breast cancer cell line MDA-MB-468, with a DC 50 value (half-degrading concentration) of 42 nM. Furthermore, XZ9002 ( Figure 7 ) efficiently suppressed clonogenic growth of T47D, HCC1143, MDA-MB-468 and BT549 breast cancer cells [ 287 ].…”

Section: Bifunctional Hdac Inhibitors For Cancer Therapymentioning

confidence: 99%

See 2 more Smart Citations

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

104

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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Section: Protacsmentioning

confidence: 99%

Section: Bifunctional Hdac Inhibitors For Cancer Therapymentioning

confidence: 99%

Section: Bifunctional Hdac Inhibitors For Cancer Therapymentioning

confidence: 99%

See 1 more Smart Citation

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

104

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“…All rights reserved Degraders targeting class I HDACs were developed using a benzamide Zn chelating group [206], including an example having moderate selectivity towards HDAC3 [207]. HDAC3 specific PROTACs were designed with benzoylhydrazide warheads exploiting a small pocket in the HDAC3 active site by occupying it with an n-propyl group, achieving DC 50 = 42 nM [208]. A recent preprint further described degraders of HDAC1, 2 and 3 based on a macrocyclic peptide [209].…”

Section: Accepted Articlementioning

confidence: 99%

Therapeutic targeting of chromatin: status and opportunities

Siklos

Kubicek

2021

The FEBS Journal

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The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

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“…Interestingly, CRL2 VHL can be hijacked by PROTACs to achieve the proteasomal degradation of non-natural substrates of this E3 ligase [ 60 , 61 ].…”

Section: Ring E3 Ligasesmentioning

confidence: 99%

Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation

et al. 2021

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Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.

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Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs

Abstract: Potent and histone deacetylase 3 (HDAC3)-specific PROTAC XZ9002 is reported here.

Cited by 73 publications

References 40 publications

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Therapeutic targeting of chromatin: status and opportunities

Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation

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