Editorial Material
Microbiology
Tom Boissavy, Dante Rotili, Thomas Mouveaux, Emmanuel Roger, El Moukthar Aliouat, Christine Pierrot, Sergio Valente, Antonello Mai, Mathieu Gissot
Summary: Toxoplasmosis is a significant health issue for immune-deficient individuals and newborns of infected mothers. New compounds with potent anti-parasitic activity have been discovered, which can serve as therapeutic targets for the treatment of toxoplasmosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Article
Chemistry, Medicinal
Yuqi Jiang, Jie Xu, Kairui Yue, Chao Huang, Mengting Qin, Dongyu Chi, Qixin Yu, Yue Zhu, Xiaohan Hou, Tongqiang Xu, Min Li, C. James Chou, Xiaoyang Li
Summary: The study focused on modifying HDAC inhibitors to deactivate the Michael reaction in order to improve their potency. Compound 11h showed significant improvements in both HDAC inhibitory activity and cell-based antitumor assay, demonstrating potential for clinical application and efficacy against AML.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Giuseppe Campiani, Caterina Cavella, Jeremy D. Osko, Margherita Brindisi, Nicola Relitti, Simone Brogi, A. Prasanth Saraswati, Stefano Federico, Giulia Chemi, Samuele Maramai, Gabriele Carullo, Benedikt Jaeger, Alfonso Carleo, Rosaria Benedetti, Federica Sarno, Stefania Lamponi, Paola Rottoli, Elena Bargagli, Carlo Bertucci, Daniele Tedesco, Daniel Herp, Johanna Senger, Giovina Ruberti, Fulvio Saccoccia, Simona Saponara, Beatrice Gorelli, Massimo Valoti, Breandan Kennedy, Husvinee Sundaramurthi, Stefania Butini, Manfred Jung, Katy M. Roach, Lucia Altucci, Peter Bradding, David W. Christianson, Sandra Gemma, Antje Prasse
Summary: The text introduces the characteristics of Idiopathic Pulmonary Fibrosis and the study related to the abnormal HDAC activities, presenting a series of hHDAC6 inhibitors as potential pharmacological tools for IPF treatment. The optimization and efficacy of new molecules were investigated for their capability in reverting the IPF phenotype.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Kai-Cheng Hsu, Jung-Chun Chu, Hui-Ju Tseng, Chia- Liu, Hao-Ching Wang, Tony Eight Lin, Hong-Sheng Lee, Ling-Wei Hsin, Andrew H-J Wang, Chien-Huang Lin, Wei-Jan Huang
Summary: The study showed that modifying the acridine ring with phenothiazine derivatives can effectively inhibit the activity of class II HDACs, with compound 4f exhibiting the strongest inhibitory effect and promoting neurite outgrowth.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Shawn J. Stachel, Deping Wang, Anthony T. Ginnetti, Shahriar Niroomand, Lei Ma, Yinghui Hu, John F. Fay, Wei Lemaire, Daniel J. Krosky, Andres D. Ramirez, Hatim A. Zariwala, Paul J. Coleman
Summary: Virtual screening was used to identify four novel, potent, and highly selective HDAC6 inhibitor series with favorable ligand binding efficiencies and good potential for further optimization.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Physical
Yogesh Mahadu Khetmalis, Bakhya Shree, Boddupalli Venkata Siva Kumar, Markus Schweipert, Cecile Debarnot, Fathima Ashna, Murugesan Sankaranarayanan, Jamma Trinath, Vivek Sharma, Franz -Josef Meyer-Almes, Kondapalli Venkata Gowri Chandra Sekhar
Summary: A series of novel tetrahydroisoquinoline (THIQ) compounds were synthesized and evaluated as selective inhibitors of histone deacetylase 6 (HDAC 6). The compounds demonstrated potent antiproliferative activities and inhibited the colony formation in cancer cells. B10 and B24 showed the highest selectivity towards HDAC 6 with IC50 values of 0.3 μM and 0.4 μM respectively. The inhibition of cancer cell proliferation by B21 and B24 was attributed to cell cycle arrest in G1 phase and apoptotic death of the cancer cells.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Biochemistry & Molecular Biology
Ping-Ting Mao, Wei-Bao He, Xi Mai, Li-Hua Feng, Na Li, Yi-Jing Liao, Cai-Sheng Zhu, Jian Li, Ting Chen, Shu-Hao Liu, Qi-Ming Zhang, Ling He
Summary: The aminobenzamide compounds with 9-substituted purine selectively inhibit class I HDACs and exhibit excellent inhibitory activity on cancer cells, particularly compound 9d. Compound 9d is 12 times more potent than MS-275 against HDAC1 isoform and has better metabolic stability compared to the well-known HDAC inhibitor SAHA.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Meran Keshawa Ediriweera
Summary: Histone acetylation is a crucial epigenetic event and continues to be an area of great interest in biochemical research. The balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs) is disrupted in various human cancers. Histone deacetylase inhibitors (HDACi) have shown promising results in restoring dysregulated histone acetylation profiles and are considered as potential anti-cancer therapeutics. Recent studies have identified odd-chain fatty acids as novel HDACi, further expanding the understanding of fatty acids in cancer therapy.
DRUG DISCOVERY TODAY
(2023)
Article
Chemistry, Multidisciplinary
Duong T. Anh, Pham-The Hai, Le D. Huy, Hoang B. Ngoc, Trinh T. M. Ngoc, Do T. M. Dung, Eun J. Park, In K. Song, Jong S. Kang, Joo-Hee Kwon, Truong T. Tung, Sang-Bae Han, Nguyen-Hai Nam
Summary: Novel N-hydroxypropenamide compounds based on 4-oxoquinazoline were designed, synthesized, and evaluated for their inhibitory and cytotoxic activities against histone deacetylase (HDAC). The derivatives with N-3-benzyl substitution showed stronger bioactivity compared to N-3-alkyl substitution. Compounds 101 and 10m exhibited the most potent HDAC inhibitory activity and cytotoxicity.
Article
Chemistry, Medicinal
Yawen Yang, Qingqing Liu, Xinyi Wang, Shaohua Gou
Summary: A series of novel histone deacetylase (HDAC) inhibitors derived from 3-(benzazol-2-yl)quinoxaline derivatives were designed and synthesized using a pharmacophore fusion strategy. In vitro studies demonstrated that most of the synthesized compounds exhibited significant anti-proliferative activity. Among them, compound 10c showed the highest cytotoxicity in HCT-116 cells with an IC50 value of 0.91 μM, surpassing Vorinostat (5.66 μM). Further investigation revealed that compound 10c up-regulated the acetylation levels of H3 and alpha-tubulin, inhibited Topo I, and induced the release of apoptotic biomarkers, highlighting its potential as a promising anti-cancer HDAC inhibitor.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Wanlin Jiang, Megan E. Block, Chandra S. Boosani
Summary: This study investigates the role of TNF-alpha and IGF-1 in regulating the epigenetic mechanisms that promote VSMCs proliferation, and identifies a novel molecular mechanism involving DNMT1, HDAC10, and HDAC2. Results reveal the inter-dependence of epigenetic mediators in VSMCs proliferation.
Review
Oncology
Robert Jenke, Nina Ressing, Finn K. Hansen, Achim Aigner, Thomas Buch
Summary: Epigenetic changes can drive cancer malignancy, while histone deacetylase inhibitors (HDACis) hold promise as anticancer drugs due to their ability to target multiple pathways relevant to the disease.
Review
Pharmacology & Pharmacy
Ekta Shirbhate, Ravichandran Veerasamy, Sai H. S. Boddu, Amit K. Tiwari, Harish Rajak
Summary: One significant obstacle in cancer treatment is the decrease in drug efficacy and occurrence of adverse effects. Oncolytic viruses (OVs) have gained interest as a potential method to treat cancer due to their specificity for cancerous tissue and reduced likelihood of adverse effects. Clinical trials have shown that OVs have an acceptable safety profile and are effective in treating certain types of cancer, despite their limited availability. However, further advancements are needed to enhance tumor permeation and improve virus delivery in order to make oncolytic virotherapy more effective.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemistry & Molecular Biology
Yuan Gao, Jilong Duan, Xiawen Dang, Yinghui Yuan, Yu Wang, Xingrui He, Renren Bai, Xiang-Yang Ye, Tian Xie
Summary: This study incorporated a polar HDACi pharmacophore into the structure of the traditional Chinese medicine anticancer drug beta-elemene, leading to the discovery of compounds 27f and 39f which exhibited potent inhibitory activity against HDACs. These compounds significantly inhibited cell proliferation and induced apoptosis in tumor cell lines, and compound 39f also caused cell cycle arrest. In vivo study validated the antitumor activity of compound 27f in a mouse model of lymphoma.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Kairui Yue, Simin Sun, Geng Jia, Mengting Qin, Xiaohan Hou, C. James Chou, Chao Huang, Xiaoyang Li
Summary: This study reports the development of a highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which exhibits superior pharmacokinetic properties compared to current hydroxamic acid inhibitors. Structure-activity relationship analysis reveals that the presence of an ethyl group substituent in the hydrazide-based ZBG and a cap group with increased rigidity and volume enhance the HDAC6 selectivity of the designed compounds. The representative inhibitor 35m demonstrates potent HDAC6 inhibitory activity and improved pharmacokinetic properties compared to hydroxamic acid-based HDAC6 inhibitors Tubastatin A and ACY1215. Furthermore, low-dose 35m effectively decreases LPS-induced IL-1 beta release by blocking the activation of NLRP3, indicating its potential as an orally active therapeutic agent for NLRP3-related diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Isabelle Wellhofer, Janina Beck, Karla Frydenvang, Stefan Brase, Christian A. Olsen
JOURNAL OF ORGANIC CHEMISTRY
(2020)
Review
Plant Sciences
Inmaculada Yruela, Carlos Moreno-Yruela, Christian A. Olsen
Summary: This review provides a comprehensive revision of plant histone deacetylase (HDA) phylogeny and translates recent lessons from other organisms. The evolution of HDAs is correlated with a gain of structural ductility/disorder, similar to other proteins. The authors highlight Brassicaceae-specific HDAs and key mutations affecting the catalytic activity of individual HDAs.
TRENDS IN PLANT SCIENCE
(2021)
Article
Multidisciplinary Sciences
Carlos Moreno-Yruela, Michael Baek, Adela-Eugenie Vrsanova, Clemens Schulte, Hans M. Maric, Christian A. Olsen
Summary: Researchers successfully captured HDAC using hydroxamic acid-modified microarray technology, providing insights into their substrate specificity and facilitating inhibitor development.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Biochemistry & Molecular Biology
Maria Duca, Dennis Gillingham, Christian Adam Olsen, Gianluca Sbardella, Philip R. Skaanderup, Mario van der Stelt, Boris Vauzeilles, Olalla Vazquez, Yves P. Auberson
Summary: The EFMC is a federation of learned societies in Europe, focusing on the dynamic field spanning chemical biology and medicinal chemistry. The organization aims to drive the development of new drug candidates through the design, synthesis, and optimization of biologically active molecules.
Article
Chemistry, Multidisciplinary
Bengt H. Gless, Benjamin S. Bejder, Fabrizio Monda, Martin S. Bojer, Hanne Ingmer, Christian A. Olsen
Summary: Research has shown that pentameric AIPs presumed to contain thiolactone structures can readily rearrange into homodetic cyclopeptides, leading to implications for a better understanding of cross-species communication in bacteria and potentially guiding the discovery of peptide ligands to disrupt their function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Carlos Moreno-Yruela, Di Zhang, Wei Wei, Michael Baek, Wenchao Liu, Jinjun Gao, Daniela Dankova, Alexander L. Nielsen, Julie E. Bolding, Lu Yang, Samuel T. Jameson, Jiemin Wong, Christian A. Olsen, Yingming Zhao
Summary: Lysine L-lactylation is a newly discovered histone modification that is stimulated under conditions of high glycolysis. Through systematic evaluation of histone deacetylases (HDACs), HDAC1-3 and SIRT1-3 were identified as delactylases for this modification. This study provides important insights into the regulatory mechanisms of histone lactylation.
Article
Chemistry, Multidisciplinary
Nima Rajabi, Tobias N. Hansen, Alexander L. Nielsen, Huy T. Nguyen, Michael Baek, Julie E. Bolding, Oskar O. Bahlke, Sylvester E. G. Petersen, Christian R. O. Bartling, Kristian Stromgaard, Christian A. Olsen
Summary: In this study, potent small molecule inhibitors targeting SIRT5 were developed, which showed selective growth inhibition of leukemia cells in culture. This work demonstrates that masked isosteres of carboxylic acids can serve as viable chemical motifs for the development of inhibitors targeting mitochondrial enzymes, with potential applications beyond the sirtuin field.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Carlos Moreno-Yruela, Christian A. Olsen
Summary: This study highlights the importance of thorough kinetic investigation in the development of selective HDAC probes. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, and this study compares the potencies and selectivities of slow-binding inhibitors measured by discontinuous and continuous assays.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Julie E. Bolding, Pablo Martin-Gago, Nima Rajabi, Luke F. Gamon, Tobias N. Hansen, Christian R. O. Bartling, Kristian Stromgaard, Michael J. Davies, Christian A. Olsen
Summary: This study demonstrates the use of aryl fluorosulfate electrophiles as covalent inhibitors targeting SIRT5, providing a potential avenue for the development of drug candidates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Bengt H. Gless, Sabrina H. Schmied, Benjamin S. Bejder, Christian A. Olsen
Summary: Thioesters are energy-rich functional groups that can react in an aqueous medium due to their hydrolytic stability at neutral pH. This study investigates the reactivity of thioesters mimicking acyl-coenzyme A (CoA) species and S-acylcysteine modifications, as well as aryl thioesters used in chemical protein synthesis. The researchers developed a fluorogenic assay to directly measure the reaction rate between thioesters and nucleophiles, and found differences in the acylation ability of acetyl- and succinyl-CoA mimics. Furthermore, the study revealed the impact of tris-(2-carboxyethyl)phosphine (TCEP) on native chemical ligation reaction conditions, including potentially harmful hydrolysis side reactions.
Article
Oncology
Dongqing Yan, Anca Franzini, Anthony D. Pomicter, Brayden J. Halverson, Orlando Antelope, Clinton C. Mason, Jonathan M. Ahmann, Anna Senina, Nadeem A. Vellore, Courtney L. Jones, Matthew S. Zabriskie, Hein Than, Michael J. Xiao, Alexandria van Scoyk, Ami B. Patel, Phillip M. Clair, William L. Heaton, Shawn C. Owen, Joshua L. Andersen, Christina M. Egbert, Julie A. Reisz, Angelo D'Alessandro, James E. Cox, Kevin C. Gantz, Hannah M. Redwine, Siddharth M. Iyer, Jamshid S. Khorashad, Nima Rajabi, Christian A. Olsen, Thomas O'Hare, Michael W. Deininger
Summary: SIRT5 is crucial for the survival and growth of AML cells, regardless of genotype, by controlling key metabolic pathways. Inhibiting SIRT5 activity is detrimental to AML cells but well tolerated by healthy hematopoietic cells, making it a potential therapeutic target for AML.
BLOOD CANCER DISCOVERY
(2021)
Article
Biochemistry & Molecular Biology
Alexander L. Nielsen, Nima Rajabi, Norio Kudo, Kathrine Lundo, Carlos Moreno-Yruela, Michael Baek, Martin Fontenas, Alessia Lucidi, Andreas S. Madsen, Minoru Yoshida, Christian A. Olsen
Summary: SIRT2 is a protein deacylase enzyme that influences diverse biological functions in the cell, making it a potential drug target for neurodegenerative diseases and cancer. Researchers have developed a series of chemical probes with potent inhibitory effects on SIRT2-mediated deacetylation and demyristoylation, providing a foundation for future therapeutic development.
RSC CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kathrin S. Troelsen, Michael Baek, Alexander L. Nielsen, Andreas S. Madsen, Nima Rajabi, Christian A. Olsen
Summary: The study developed a strategy for selectively inhibiting SIRT3 in cells by incorporating mitochondria-targeting peptide sequences into inhibitor structures, demonstrating excellent mitochondrial localization in HeLa cells and target engagement through a cellular thermal shift assay. This selective inhibition showed increased acetylation of the documented SIRT3 target MnSOD in cells, indicating potential for further investigation of SIRT3 as a drug target.
RSC CHEMICAL BIOLOGY
(2021)
Article
Biochemical Research Methods
Carlos Moreno-Yruela, Christian A. Olsen
Summary: Histone deacetylases (HDACs) are enzymes that cleave post-translational e-N-acyllysine modifications. A high-throughput screening protocol is described to identify deacylase activities, with careful optimization of continuous enzyme assays to determine kinetic parameters efficiently. These techniques can aid in inhibitor assay design and provide fundamental understanding of HDAC biochemistry.
Article
Chemistry, Medicinal
Timothy Lynagh, Stephan Kiontke, Maria Meyhoff-Madsen, Bengt H. Gless, Jonas Johannesen, Sabrina Kattelmann, Anders Christiansen, Martin Dufva, Andreas H. Laustsen, Kanchan Devkota, Christian A. Olsen, Daniel Kuemmel, Stephan Alexander Pless, Brian Lohse
JOURNAL OF MEDICINAL CHEMISTRY
(2020)