Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)

Cao, Fangyuan; Weerd, Sander de; Chen, Deng; Zwinderman, Martijn R. H.; Wouden, Petra E van der; Dekker, Frank J.

doi:10.1016/j.ejmech.2020.112800

Cited by 56 publications

(58 citation statements)

References 30 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%

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

Jenke

Reßing

Hansen

et al. 2021

Cancers

107

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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%

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

Jenke

Reßing

Hansen

et al. 2021

Cancers

107

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“…Moreover, degraders, as tool molecules for chemical knockdown, provide an opportunity to help differentiate the enzymatic and scaffolding functions of HDAC proteins. Although degraders for HDAC6 (An et al, 2019;Dorman et al, 2018;Sinatra et al, 2020;Yang et al, 2020) and class I HDACs (Cao et al, 2020;Smalley et al, 2020; have been reported to date, no systematic investigation into the degradability of the HDAC family and the consequences of HDAC degradation on HDAC-containing complexes has been pursued. To thoroughly explore the accessibility and degradability of HDACs, we designed and synthesized a comprehensive library of 48 multi-HDAC-targeting degrader molecules incorporating four different pan-HDAC binding warheads chemically linked to recruiters of three different ubiquitin E3 ligases: CRBN, von Hippel-Lindau (VHL), and inhibitor of apoptosis proteins (IAP).…”

Section: Introductionmentioning

confidence: 99%

Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Xiong

Donovan

Eleuteri

et al. 2021

Cell Chemical Biology

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“…This article is protected by copyright. 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].…”

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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Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)

Cited by 56 publications

References 30 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

Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Therapeutic targeting of chromatin: status and opportunities

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