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
Biochemistry & Molecular Biology
Wenli Fan, Lin Zhang, Xuejiang Wang, Haiyong Jia, Lei Zhang
Summary: In this study, pharmacophores of phenanthridine were incorporated into HDAC inhibitors, and fatty and aromatic linkers were evaluated for solubility and activity. Compounds with aromatic linker showed better activities than those with fatty linker. Molecule Fb-4 exhibited promising anticancer potency by inducing G2/M phase arrest and apoptosis in MCF-7 cells, suggesting its potential as a lead compound for further drug design.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yiming Chen, Lihui Zhang, Lin Zhang, Qixiao Jiang, Lei Zhang
Summary: Through structural modification, a HDAC inhibitor (I13) with high anticancer activity was discovered, showing promising inhibitory and antiproliferative potencies in in vitro investigations and cancer cell screenings. The compound also demonstrated potential for inhibiting tumor growth in animal models.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Carlo Baggio, Anna Kulinich, Cassandra N. Dennys, Rochelle Rodrigo, Kathrin Meyer, Iryna Ethell, Maurizio Pellecchia
Summary: The study utilized an innovative NMR-guided screening and ligand design approach to derive low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands. These agents demonstrated nanomolar affinity, activated receptors in cellular assays with motor neurons, and provided significant motor neuron protection from ALS patient-derived astrocytes. Structural studies on the complex between the ligand-binding domain and the most active agent offered insights into the agents' mechanism at a molecular level, forming a strong foundation for potential treatment of ALS and other human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
Zhuang Li, Yahui Huang, Jie Tu, Wanzhen Yang, Na Liu, Wei Wang, Chunquan Sheng
Summary: Invasive fungal infections, particularly candidiasis, have become a significant cause of morbidity and mortality due to lack of effective antifungal drugs and drug resistance. A new class of BRD4-histone deacetylase (HDAC) inhibitors has been designed to restore susceptibility of Candida albicans to fluconazole. One compound, B2, has shown excellent selectivity against fungal HDACs, synergistic effect with fluconazole, and low cytotoxicity. In vivo studies have demonstrated that B2, in combination with fluconazole, effectively reduces fungal loads and prevents biofilm formation and morphological changes in resistant C. albicans, suggesting its potential for treating resistant candidiasis.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Chen Chen, Xue Li, Huajun Zhao, Meng Liu, Jintong Du, Jian Zhang, Xinying Yang, Xuben Hou, Hao Fang
Summary: The combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor has shown a synergistic antiproliferation effect. A new series of benzimidazole-hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities but also showed potent antiproliferation activities against tumor cells. Importantly, these compounds demonstrated good in vivo antitumor efficacies and reshaped the tumor immune microenvironment by promoting antigen presentation, activating T cells, and polarizing tumor-infiltrating macrophages with antitumor activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Daqiang Li, Zhuo Zhang, Yalei Li, Xinyi Wang, Hanyue Zhong, Huajie Yang, Yong Xi, Hongchun Liu, Aijun Shen, Youhong Hu
Summary: A series of novel benzamide derivatives were designed and synthesized from the pyridazinone scaffold. Among them, (S)-17b showed potent inhibitory activity against human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line in vitro. Furthermore, (S)-17b demonstrated excellent in vivo antitumor activity in SKM-1 xenograft models, and showed better efficacy on mouse models with intact immune system compared to those with thymus deficiencies. This novel compound (S)-17b may serve as a promising drug candidate for further investigation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
J. Miguel Mata, Edith van der Nol, Sebastian J. J. Pomplun
Summary: Discovering new bioactive molecules is crucial for drug development, and affinity selection based technologies have revolutionized the hit discovery process. Recent breakthroughs in screening ultralarge synthetic peptidomimetic libraries using barcode-free tandem mass spectrometry decoding have enabled hit discovery from libraries with over 100 million members. This technology combines combinatorial synthesis, affinity selection, automated de novo peptide sequencing algorithms, and advances in mass spectrometry instrumentation. Success stories include the discovery of high affinity binders for various drug targets and specific functions and reactivity of synthetic peptidomimetics. This technology is predicted to rapidly evolve and become a broadly used drug discovery technology.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Xuewu Liang, Shuai Tang, Xuyi Liu, Yingluo Liu, Qifu Xu, Xiaomin Wang, Abdusaid Saidahmatov, Chunpu Li, Jiang Wang, Yu Zhou, Yingjie Zhang, Meiyu Geng, Min Huang, Hong Liu
Summary: This study discovered a series of potential JAK and HDAC dual inhibitors that showed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. These compounds also demonstrated the ability to overcome drug resistance caused by the tumor microenvironment.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Ye Sheng, Tingting Deng, Pengfei Qiu, Xun Shi, Jinyang Xi, Yuexing Han, Jiong Yang
Summary: This study presents an example of using high-throughput methods to search for novel Cu-Sn-S ternary thermoelectric materials, involving synthesis, characterization, and analysis. Different strategies were proposed to classify different areas in the images and two interesting thermoelectric phases, Cu7Sn3S10 and Cu1.6S, were identified with potential for high thermoelectric efficiency.
CHEMISTRY OF MATERIALS
(2021)
Article
Oncology
Qian Zhao, Shan-Shan Xiong, Can Chen, Hong-Ping Zhu, Xin Xie, Cheng Peng, Gu He, Bo Han
Summary: The authors designed and synthesized a series of compounds with dual inhibitory activity against MDM2 and HDAC, and found that compound 11b exhibited the strongest inhibition against both targets. This compound also showed effective antiproliferative activity towards MCF-7 cells and increased the expression of p53 and Ac-H4. These results suggest that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drugs in the future.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xue Zhong, Huiwen Deng, Min Long, Honglu Yin, Qiu Zhong, Shilong Zheng, Tao Gong, Ling He, Guangdi Wang, Qiu Sun
Summary: Berberine was discovered as a potent p300/CBP HAT inhibitor and showed inhibition of tumor growth. Novel analog 5d, derived from berberine, demonstrated high selectivity towards p300/CBP HAT and effectively suppressed tumor growth in animal models. Furthermore, liposomes-encapsulated 5d showed increased inhibition of tumor growth with good absorption properties in vivo.
BIOORGANIC CHEMISTRY
(2023)
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
Michael Baek, Pablo Martin-Gago, Jonas S. Laursen, Julie L. H. Madsen, Saswati Chakladar, Christian A. Olsen
CHEMISTRY-A EUROPEAN JOURNAL
(2020)
Article
Chemistry, Medicinal
Nima Rajabi, Alexander L. Nielsen, Christian A. Olsen
ACS MEDICINAL CHEMISTRY LETTERS
(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.