Article
Biochemistry & Molecular Biology
Kendra R. Vann, Brianna J. Klein, Tatiana G. Kutateladze
Summary: This review discusses the rapid advances in the identification and characterization of epigenetic readers in the past two decades, as well as the emergence of new readers capable of interacting with the nucleosome through binding to both histones and DNA. The mechanistic insights underlying bivalent histone and DNA recognition by newly characterized readers are explored, emphasizing the importance of DNA binding for their association with chromatin.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Review
Chemistry, Multidisciplinary
Md Kabir, Xufen Yu, H. Umit Kaniskan, Jian Jin
Summary: Proteolysis-targeting chimeras (PROTACs) are small molecules that induce targeted degradation of proteins by forming ternary complexes with E3 ligases. They have the advantage of targeting both canonical and noncanonical functions of epigenetic targets, resulting in greater therapeutic efficacy. This review analyzes published PROTAC degraders of epigenetic writer, reader, and eraser proteins and discusses their mechanism of action and advantages in cancer treatment. Overall, pharmacological degradation of epigenetic targets has emerged as an effective strategy against cancer.
CHEMICAL SOCIETY REVIEWS
(2023)
Article
Chemistry, Medicinal
Siqi Guo, Tongguan Jia, Xiaoming Xu, Feng Yang, Senhao Xiao, Zeng Hou, Hesong Xu, Shuyuan Ma, Xiao Liu, Cheng Luo, Hualiang Jiang, Hua Chen, Shijie Chen
Summary: In this study, a series of compounds were designed and synthesized based on structural optimization of SGC-iMLLT. The most potential compounds were found to have strong ENL inhibitory activities and could interact with ENL protein, enhancing its thermal stability. Compound 28 exhibited significant inhibitory activities against leukemia cell lines and downregulated the expression of target gene MYC. In addition, compound 28 showed improved pharmacokinetic properties compared to SGC-iMLLT, making it a potential ligand for ENL-related MLL chemotherapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Sha Liu, Xiang Li, Xin Li, Xiang David Li
Summary: Inhibitors targeting epigenetic readers serve as useful probes to study the functional roles of these targets in epigenetic regulation, and can also be used as drugs for treating diseases associated with dysregulated targets. However, many epigenetic readers are difficult to target with small molecules due to their recognition of modified histone peptides, which commonly involves flat and extended protein surfaces. Peptide-based inhibitors have larger sizes and structural complexity, allowing for tight and specific binding to the target proteins. This review discusses the recent advances in peptide-based inhibitors for lysine acetylation and methylation readers.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Robin Warstat, Mehrosh Pervaiz, Pierre Regenass, Marius Amann, Karin Schmidtkunz, Oliver Einsle, Manfred Jung, Bernhard Breit, Martin Huegle, Stefan Guenther
Summary: For a long time, BD inhibitors were mainly related to the BET family, but now inhibitors for BDs outside the BET family have been developed. We present a new pan-BD inhibitor that shows affinity to various BDs and exhibits broad activity against different cancer cell lines. Through modifications, we were able to control the selectivity of the inhibitor and make it a highly selective BRD9 inhibitor.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Cell Biology
Zetao Ma, Lei Chen, Yushun Wang, Sheng Zhang, Jianrui Zheng, Yuhong Luo, Chao Wang, Hui Zeng, Lixiang Xue, Zhen Tan, Deli Wang
Summary: Degenerative musculoskeletal diseases, such as osteoporosis, osteoarthritis, degenerative spinal disease, and sarcopenia, have a significant impact on bone, cartilage, and muscle tissues, leading to functional impairment and pain. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, plays a crucial role in the development of these diseases through the epigenetic regulation of gene expression. The pharmacological inhibition of EZH2 holds promise as a potential therapeutic approach for improving the treatment of degenerative musculoskeletal diseases.
AGEING RESEARCH REVIEWS
(2023)
Article
Chemistry, Medicinal
Xixi Fang, Jinhong Feng, Kewei Wang, Yepeng Luan
Summary: Through structure analysis, we designed three analogs of VER-50589 which showed strong inhibitory activity against Hsp90. Among them, compound 12-1 exhibited the most potent inhibitory activity with IC50 value of 9 nM. In tumor cell experiments, 12-1 effectively suppressed cell proliferation, induced apoptosis, and arrested cell cycle in G0/G1 phase. Western blotting showed downregulation of Hsp90 client proteins CDK4 and HER2. Molecular dynamic simulation confirmed the binding of 12-1 to Hsp90 ATP-binding site.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Health Care Sciences & Services
Mohammed Ghiboub, Ahmed M. I. Elfiky, Menno P. J. de Winther, Nicola R. Harker, David F. Tough, Wouter J. de Jonge
Summary: Selective inhibition of HDACs and BCPs has become a focus in drug discovery, aiming to elucidate individual functions of epigenetic modulators and develop safer therapeutic strategies. Recent advances have shown that more selective inhibitors can mimic the benefits of pan-inhibitors with reduced adverse events. Multiple in vitro and in vivo studies support the potential of these strategies for treating autoimmune and inflammatory diseases.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Xiaoqing Xie, Daria Frank, Pradeep Kumar Patnana, Judith Schuette, Yahya Al-Matary, Longlong Liu, Lanying Wei, Martin Dugas, Julian Varghese, Subbaiah Chary Nimmagadda, Cyrus Khandanpour
Summary: The study identified a therapeutic role for curcumin treatment in delaying the expansion of GFI1-36N or -KD, NUP98-HODXD13 leukemic cells and prolonging AML-free survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Jee Hoon Song, Alan H. Tieu, Yulan Cheng, Ke Ma, Venkata S. Akshintala, Cem Simsek, Vishnu Prasath, Eun Ji Shin, Saowanee Ngamruengphong, Mouen A. Khashab, John M. Abraham, Stephen J. Meltzer
Summary: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). In this study, the long noncoding RNA (lncRNA) miR205HG was identified as a tumor suppressor in BE and EAC development, partly through its impact on the Hedgehog signaling pathway. The overexpression of miR205HG inhibits EAC cell proliferation in vitro and xenograft tumor growth in mice in vivo, while also influencing the Hh signaling pathway.
Article
Multidisciplinary Sciences
Xing -Xing Dai, Shuai-Bo Pi, Long -Wen Zhao, Yun-Wen Wu, Jing-Ling Shen, Song-Ying Zhang, Qian-Qian Sha, Heng-Yu Fan
Summary: This study reveals the formation of non-membrane-bound nuclear poly(A) domains (NPAD) as the hub for newly transcribed mRNA in developing mouse oocytes. These NPAD are essential for the development of oocytes and female reproduction.
Article
Biochemistry & Molecular Biology
Hyejin Kim, Inkyung Jung, Chan Hyeong Lee, Jungeun An, Myunggon Ko
Summary: Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. This study identified mitoxantrone as a potent TET activator, which increased 5hmC levels and induced tumor cell death by restoring TET activity. These findings highlight the potential of targeted epigenetic therapies in cancer treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Genetics & Heredity
Jing Feng, Yahui Gao, Kun Wang, Mingguo Jiang
Summary: ZRF1, an epigenetic regulator, plays a key role in transcriptional regulation by binding to monoubiquitinated histone H2A in animals and humans, and acts as a tumor suppressor. The homologs of ZRF1 are widely found in plants, but studies on ZRF1 in higher plants are limited.
Article
Pharmacology & Pharmacy
Zhifu Xie, Mei Zhang, Qian Song, Long Cheng, Xinwen Zhang, Gaolei Song, Xinyu Sun, Min Gu, Chendong Zhou, Yangming Zhang, Kexin Zhu, Jianpeng Yin, Xiaoyan Chen, Jingya Li, Fajun Nan
Summary: In this study, a novel ACLY inhibitor, 326E, was developed and showed promising results in reducing hepatic cholesterol accumulation and improving hyperlipidemia. It inhibited de novo lipogenesis and increased cholesterol efflux both in vitro and in vivo. The compound exhibited higher blood exposure and better therapeutic efficacy compared to the approved ACLY inhibitor bempedoic acid (BA).
ACTA PHARMACEUTICA SINICA B
(2023)
Review
Biochemistry & Molecular Biology
Jorseth Rodelo Gutierrez, Arturo Rene Mendoza Salgado, Marcio De Avila Arias, Homero San-Juan-Vergara, Wendy Rosales Rada, Carlos Mario Melendez Gomez
Summary: This article discusses the importance of chromatin and its changes in controlling gene expression, particularly in cancer. Studies have shown that DNA methylation, histone modifications, chromatin remodeling, and miRNA-mediated gene silencing play crucial roles in various diseases, including cancer.
CURRENT MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jianwei Lin, Xiucong Bao, Xiang Li David
Summary: The study introduces a new method, ADdis-Cys-MS, that can successfully identify PTM readers and map their PTM recognition modules simultaneously. Using this method, several binding sites of reader-PTM interactions were identified, including a novel histone chaperone.
Review
Chemistry, Multidisciplinary
Xin Li, Xiang David Li
Summary: The hereditary blueprint of a eukaryotic cell is encoded in genomic DNA compacted into chromatin with histone proteins. Histone posttranslational modifications (PTMs) regulate DNA-templated processes and are associated with human disease pathogenesis. The dynamic fluctuations of histone PTMs emphasize the importance of fully deciphering the histone code.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Yixiang Jiang, Sha Liu, Gaofei Tian, Hayden Jit Hei Cheung, Xin Li, Xiang David Li
Summary: The new synthesis method significantly reduced the time required for the preparation of YEATS domain-selective cyclopeptide inhibitors and led to a higher overall yield. Furthermore, the new synthetic route allowed further derivatisation of the cyclopeptides with various functional modules, including conjugation with cell-penetrating peptide.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Yihang Jing, Xin Li, Zheng Liu, Xiang David Li
Summary: The nucleosome is the basic repeating unit of chromatin, with histone posttranslational modifications playing a key role in nucleosome structure and dynamics. Newly identified negatively charged histone lysine acylations have been shown to significantly influence nucleosome and chromatin dynamics.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Zhuoyuan Zhang, Jianwei Lin, Zheng Liu, Gaofei Tian, Xiao-Meng Li, Yihang Jing, Xin Li, Xiang David Li
Summary: This article reviews recent advances in using photo-crosslinking strategies to investigate the epigenetic interactome, focused on the protein-protein interactions mediated by epigenetic marks in histone tails. The future directions include developing photo-crosslinking-based tools and methods for studying binding events in nucleosomal/chromatinic contexts, and for capturing the epigenetic interactome in live cells or even organisms.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Xiao-Meng Li, Siyue Huang, Xiang David Li
Summary: Bacterial pathogens adapt their proteome to survive in host cells and secrete effector proteins to manipulate host targets. Conventional proteomics struggles to profile pathogen proteome dynamics due to excessive host proteins. Mapping pathogen-host protein-protein interactions is challenging due to low abundance and transient interactions of bacterial effectors. A new method using a bifunctional amino acid, photo-ANA, allows selective labeling of bacterial proteomes and simultaneous analysis of proteome reprogramming and pathogen-host interactions during Salmonella infection.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jianwei Lin, Yiping Wu, Gaofei Tian, Daqi Yu, Eunjeong Yang, Wai Hei Lam, Zheng Liu, Yihang Jing, Shangyu Dang, Xiucong Bao, Jason Wing Hon Wong, Yuanliang Zhai, Xiang David Li
Summary: H3K79me2 is an important epigenetic mark involved in gene regulation, cellular differentiation, and disease progression. A nucleosome-based photoaffinity probe was used to identify menin as a reader of H3K79me2 in a nucleosomal context. Cryo-electron microscopy showed that menin interacts with the nucleosome through specific domains and recognizes the methylation mark through a p-cation interaction. In cells, menin is selectively associated with H3K79me2 on chromatin, particularly in gene bodies.
Article
Multidisciplinary Sciences
Zheng Liu, Yiping Wu, Xin Mao, Ka Chun Jonathan Kwan, Xinxin Cheng, Xin Li, Yihang Jing, Xiang David Li
Summary: Various proteins bind to chromatin to regulate DNA processes. This study developed a protein labeling chemistry to prepare synthetic nucleosomes that carry functional groups for examining chromatin-protein interactions. The prepared probes were used to study protein-protein and protein-nucleosome interactions, mapping binding sites and identifying specific proteins associated with nucleosomes. This study provides versatile chemical tools for investigating chromatin-associating proteins.
Review
Biochemistry & Molecular Biology
Sha Liu, Xiang Li, Xin Li, Xiang David Li
Summary: Inhibitors targeting epigenetic readers serve as useful probes to study the functional roles of these targets in epigenetic regulation, and can also be used as drugs for treating diseases associated with dysregulated targets. However, many epigenetic readers are difficult to target with small molecules due to their recognition of modified histone peptides, which commonly involves flat and extended protein surfaces. Peptide-based inhibitors have larger sizes and structural complexity, allowing for tight and specific binding to the target proteins. This review discusses the recent advances in peptide-based inhibitors for lysine acetylation and methylation readers.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Yihang Jing, Zheng Liu, Xiang David Li
Summary: Lysine succinylation is a crucial posttranslational modification that plays important roles in metabolism, epigenetic signaling, and human diseases. Investigating the effects of succinyl lysine on nucleosome dynamics requires the generation of uniformly modified histones, which is a challenge. By rapidly installing a succinyl lysine analog and using a Förster resonance energy transfer approach, the impact on nucleosome dynamics can be characterized.
