ArticleBiochemistry2023
Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).
Article in Biochemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Histone Deacetylase Meets Protein Degradation: Accelerating Anticancer Drug Discovery.Medicinal research reviews · 2026Review
- Dual PROTACs Versus Dual Inhibitors in Oncology: A Medicinal Chemistry and Linker Design Perspective.Pharmaceuticals (Basel, Switzerland) · 2026Review
- HDAC3 in Alzheimer's Disease: established evidence, unresolved questions, and translational priorities.Molecular biology reports · 2026Review
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- FOXO: a key target in regulating aging and age-related diseases.Biogerontology · 2026Review
- Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation.Nucleic acids research · 2025Article
- FoxO3 Activation Alleviates Doxorubicin-Induced Cardiomyopathy by Enhancing Autophagic Flux and Suppressing mTOR/ROS Signalling.Journal of cellular and molecular medicine · 2025Article
- Targeted Degradation of Class 1 HDACs With PROTACs is Highly Effective at Inducing DLBCL Cell Death.EJHaem · 2025Article
- Rapid degradation of histone deacetylase 1 (HDAC1) reveals essential roles in both gene repression and active transcription.Nucleic acids research · 2025Article
- Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system.Science advances · 2025Article
- Applications of protein ubiquitylation and deubiquitylation in drug discovery.The Journal of biological chemistry · 2024Review
- Histone deacetylases maintain expression of the pluripotent gene network via recruitment of RNA polymerase II to coding and noncoding loci.Genome research · 2024Article
- Degraders in epigenetic therapy: PROTACs and beyond.Theranostics · 2024Review
- Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation.Cell chemical biology · 2023Article
- PROTAC chemical probes for histone deacetylase enzymes.RSC chemical biology · 2023Review
- Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.Nature structural & molecular biology · 2023Article
- Targeting histone deacetylases for cancer therapy: Trends and challenges.Acta pharmaceutica Sinica. B · 2023Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The class I histone deacetylase (HDAC) enzymes;HDAC1,2 and 3 form the catalytic engine of at least seven structurally distinct multiprotein complexes in cells. These molecular machines play a vital role in the regulation of chromatin accessibility and gene activity via the removal of acetyl moieties from lysine residues within histone tails. Their inhibition via small molecule inhibitors has beneficial effects in a number of disease types, including the clinical treatment of hematological cancers. We have previously reported a library of proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase that degrade HDAC1-3 at submicromolar concentrations. Here we report the addition of two novel PROTACs (JPS026 and JPS027), which utilize a ligand for the cellular inhibitor of apoptosis (IAP) family of E3 ligases. We found that both VHL (JPS004)- and IAP (JPS026)-based PROTACs degrade HDAC1-3 and induce histone acetylation to a similar degree. However, JPS026 is significantly more potent at inducing cell death in HCT116 cells than is JPS004. RNA sequencing analysis of PROTAC-treated HCT116 cells showed a distinct gene expression signature in which cell cycle and DNA replication machinery are repressed. Components of the mTORC1 and -2 complexes were also reduced, leading to an increase in FOXO3 and downstream target genes that regulate autophagy and apoptosis. In summary, a novel combination of HDAC and IAP ligands generates a PROTAC with a potent ability to stimulate apoptosis and differential gene expression in human cancer cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.