Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases DOI
Margherita Brindisi, A. Prasanth Saraswati, Simone Brogi

et al.

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 63(1), P. 23 - 39

Published: Aug. 15, 2019

Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond well-characterized histone modifiers, HDACs also interact with several nonhistone substrates increased expression has been highlighted diseases. The HDAC6 isoform, due its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, peroxiredoxins. exerts noncatalytic activities through interaction ubiquitin. Both catalytic functions are being actively studied field rare disorders beyond well-established carcinogenesis. This Perspective outlines application HDAC(6) inhibitors diseases, such Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, Charcot–Marie–Tooth disease, highlighting potential innovative targeted disease-modifying agents.

Language: Английский

Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view DOI
Navriti Chadha, Om Silakari

European Journal of Medicinal Chemistry, Journal Year: 2017, Volume and Issue: 134, P. 159 - 184

Published: April 5, 2017

Language: Английский

Citations

525
Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics DOI
Ibraheem Ali,

Ryan J. Conrad,

Eric Verdin

et al.

Chemical Reviews, Journal Year: 2018, Volume and Issue: 118(3), P. 1216 - 1252

Published: Feb. 6, 2018

Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered 1963 unique modification histones, marks are now found on thousands nonhistone proteins located virtually every cellular compartment. Here we summarize findings the field protein over past 20 years with focus recent discoveries nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these have elevated major post-translational modification, underscoring its physiological relevance gene regulation, cell signaling, metabolism, disease.

Language: Английский

Citations

306
Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability DOI Open Access
Giorgio Milazzo, Daniele Mercatelli, Giulia Di Muzio

et al.

Genes, Journal Year: 2020, Volume and Issue: 11(5), P. 556 - 556

Published: May 15, 2020

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling gene expression profiles. We provide here a review the recent knowledge accrued zinc-dependent HDAC family across different species, tissues, human pathologies, specifically focusing role of inhibitors as anti-cancer agents. will investigate chemical specificity HDACs discuss their in interactome members chromatin-binding complexes.

Language: Английский

Citations

275
The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy DOI Creative Commons
Li Guo, Yuan Tian, Wei‐Guo Zhu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Sept. 29, 2020

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units chromatin. The fifth amino group (Nε) lysine residues is a common site for post-translational modifications (PTMs), these, acetylation second most common. Histone modulated by acetyltransferases (HATs) deacetylases (HDACs), involved in expression. Over past two decades, numerous studies characterizing HDACs HDAC inhibitors (HDACi) have provided novel exciting insights concerning their biological potential anti-cancer treatments. In this review, we detail diverse structures functions, including transcriptional regulation, metabolism, angiogenesis, damage response, cell cycle, apoptosis, protein degradation, immunity other several physiological processes. We also highlight avenues to use HDACi as novel, precision cancer

Language: Английский

Citations

271
Acetylation of intrinsically disordered regions regulates phase separation DOI
Makoto Saito, Daniel Heß, Jan Eglinger

et al.

Nature Chemical Biology, Journal Year: 2018, Volume and Issue: 15(1), P. 51 - 61

Published: Nov. 28, 2018

Language: Английский

Citations

255
Targeting Metalloenzymes for Therapeutic Intervention DOI
Allie Y. Chen,

Rebecca N. Adamek,

Benjamin L. Dick

et al.

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(2), P. 1323 - 1455

Published: Sept. 7, 2018

Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role metalloenzymes in these processes also makes them for the progression diseases and, as such, attractive targets therapeutic intervention. Increasing awareness play disease their importance class has amplified interest development new strategies develop inhibitors ultimately useful drugs. In this Review, we provide broad overview several drug discovery efforts focused on attempt map out current landscape high-value metalloenzyme targets.

Language: Английский

Citations

234
ARID1A-mutated ovarian cancers depend on HDAC6 activity DOI
Benjamin G. Bitler, Shuai Wu, Pyoung Hwa Park

et al.

Nature Cell Biology, Journal Year: 2017, Volume and Issue: 19(8), P. 962 - 973

Published: July 24, 2017

Language: Английский

Citations

209
HDAC6 as privileged target in drug discovery: A perspective DOI
Sravani Pulya, Sk. Abdul Amin, Nilanjan Adhikari

et al.

Pharmacological Research, Journal Year: 2020, Volume and Issue: 163, P. 105274 - 105274

Published: Nov. 7, 2020

Language: Английский

Citations

190
Histone deacetylase 10 structure and molecular function as a polyamine deacetylase DOI Creative Commons
Yang Hai, Stephen A. Shinsky, Nicholas J. Porter

et al.

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: May 18, 2017

Abstract Cationic polyamines such as spermidine and spermine are critical in all forms of life, they regulate the function biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation dysregulated associated with neoplastic diseases colon cancer, prostate cancer neuroblastoma. Here we report that histone deacetylase 10 (HDAC10) a robust deacetylase, using recombinant enzymes from Homo sapiens (human) Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure zebrafish HDAC10 complexed transition-state analogue inhibitor reveals glutamate gatekeeper sterically constricted active site confer specificity for N 8 -acetylspermidine hydrolysis disfavour acetyllysine hydrolysis. Both known to promote cellular survival through autophagy. Accordingly, this work sets foundation studying chemical biology autophagy structure-based design inhibitors may also serve new leads chemotherapy.

Language: Английский

Citations

180
Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives DOI Open Access
Robert Jenke,

Nina Reßing,

Finn K. Hansen

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(4), P. 634 - 634

Published: Feb. 5, 2021

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

Language: Английский

Citations

139