Article
Biochemistry & Molecular Biology
Diletta Ciardo, Olivier Haccard, Hemalatha Narassimprakash, David Cornu, Ida Chiara Guerrera, Arach Goldar, Kathrin Marheineke
Summary: This study demonstrates that Plk1 plays a crucial role in regulating replication origin firing during the non-challenged S phase through interactions with various factors. By analyzing the effects of Plk1 depletion on replication fork density and initiation frequency, as well as its interaction with Rif1 and other firing factors, the study provides insights into how Plk1 controls the activation of origins at the level of large chromatin domains in vertebrates.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Diletta Ciardo, Olivier Haccard, Hemalatha Narassimprakash, David Cornu, Ida Chiara Guerrera, Arach Goldar, Kathrin Marheineke
Summary: The study reveals that Plk1 strictly controls the activation of replication origins at multiple steps, reducing the probability and synchrony of activation, and regulates DNA replication by interacting with multiple firing factors and replication timing regulators.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Medicinal
Danda Chapagai, Gurusankar Ramamoorthy, Jessy Varghese, Elmar Nurmemmedov, Campbell McInnes, Michael D. Wyatt
Summary: PLK1, a key regulator of mitosis, can be effectively inhibited by abbapolins through targeting its PBD, leading to potent antiproliferative activity. Moreover, abbapolins demonstrate specific binding and inhibitory activity against PLK1, along with strong antiproliferative effects in cells resistant to ATP-competitive inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Jessy M. Stafford, Michael D. Wyatt, Campbell McInnes
Summary: Polo Like Kinase 1 (PLK1) is often overexpressed in human cancers and is associated with poor survival rates, making it a potential target for cancer therapeutic development. In this review, the rationale for targeting the PBD over the ATP binding site is discussed, along with recent progress, challenges, and outlook.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Multidisciplinary Sciences
Priyanka Parijat, Saraswathi Ponnam, Seetharamaiah Attili, Kenneth S. Campbell, Mohammed El-Mezgueldi, Mark Pfuhl, Thomas Kampourakis
Summary: The unmet demand for new heart failure therapeutics is well recognized and targeting the contractile myofilaments has shown potential for the development of new drugs. However, limited clinical use and incomplete understanding of myofilament function have hindered progress in this area. In this study, new high throughput screening platforms were designed and validated to explore the effects of small molecule effectors on the interactions between cardiac troponin C and troponin I subunits. The results suggest that sarcomeric protein-directed screening platforms are suitable for developing compounds that modulate cardiac myofilament function.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Sheng Yan, Bin Peng, Shifeng Kan, Guangcan Shao, Zhikai Xiahou, Xiangyan Tang, Yong-Xiang Chen, Meng-Qiu Dong, Xiao Liu, Xingzhi Xu, Jing Li
Summary: This article investigates the impact of O-GlcNAc transferase (OGT) on PLK1, and finds that OGT can modify PLK1 through O-GlcNAcylation. Further research reveals that the T291A and T291N mutations increase the stability of PLK1 and lead to chromosome segregation defects and uterine carcinoma. The findings suggest that OGT exerts its mitotic function partially through O-GlcNAcylation of PLK1, which may contribute to tumorigenesis by elevating O-GlcNAc levels.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Christopher A. Raab, Monika Raab, Sven Becker, Klaus Strebhardt
Summary: This article discusses the important roles of PLK1-5 in regulating non-mitotic signaling, as well as the potential of PLK1 and PLK4 as cancer targets. It highlights the need for specific ATP-competitive inhibitors for PLK4 and PLK1, as well as the unique druggable domain, the polo-box-domain (PBD), that offers the opportunity for the development of inhibitors targeting only PLKs.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Microbiology
Sujin Jung, Hye Seon Lee, Ho-Chul Shin, Joon Sig Choi, Seung Jun Kim, Bonsu Ku
Summary: Human papillomaviruses (HPVs) are responsible for HPV-driven abnormalities such as cervical cancer or benign warts by promoting infected cell proliferation. Most HPVs can be classified into three major genera: Alphapapillomavirus, Betapapillomavirus, and Gammapapillomavirus. The L2 protein of HPVs plays a role in viral capsid formation and interacts with human proteins during viral infection. The study revealed that the L2 protein of HPV16 recruits polo-like kinase 1 (Plk1) for the delivery of viral DNA to mitotic chromatin, and Plk1 interacts with L2 proteins of various HPV genotypes.
JOURNAL OF MICROBIOLOGY
(2023)
Article
Chemistry, Analytical
Qian Kong, Yicheng Weng, Zhendong Zheng, Wendong Chen, Pengfei Li, Zongwei Cai, Ruijun Tian
Summary: Tyrosine phosphorylation plays a crucial role in signaling pathways, but its systematic analysis is challenging due to its low abundance and transient nature. In this study, a 96-well microplate-based approach was developed to simplify the pTyr peptide enrichment workflow and showed high sensitivity and reproducibility.
ANALYTICAL CHEMISTRY
(2022)
Article
Nanoscience & Nanotechnology
Prakash Shrestha, Darren Yang, Toma E. Tomov, James MacDonald, Andrew Ward, Hans T. Bergal, Elisha Krieg, Serkan Cabi, Yi Luo, Bhavik Nathwani, Alexander Johnson-Buck, William M. Shih, Wesley P. Wong
Summary: DNA nanoswitch calipers can measure distances within single molecules with atomic resolution, enabling identification and quantification of molecules in trace samples via mechanical fingerprinting. Through the combination of DNA nanotechnology and single-molecule force spectroscopy, these calipers offer a powerful tool for characterizing distances within nanoscale complexes, with applications in fields such as single-molecule proteomics.
NATURE NANOTECHNOLOGY
(2021)
Article
Chemistry, Medicinal
Jung-Eun Park, Hobin Lee, Paola Oliva, Klara Kirsch, Bora Kim, Jong Il Ahn, Celeste N. Alverez, Snehal Gaikwad, Kristopher W. Krausz, Robert O'Connor, Ganesha Rai, Anton Simeonov, Beverly A. Mock, Frank J. Gonzalez, Kyung S. Lee, Kenneth A. Jacobson
Summary: Polo-like kinase 1 (Plk1) is an attractive target for anticancer drug discovery due to its widely upregulated activity in various human cancers. In addition to the kinase domain, the C-terminal noncatalytic polo-box domain (PBD) has emerged as an alternative target for developing inhibitors. Triazoloquinazolinone-derived inhibitors effectively block Plk1 with improved affinity and drug-like properties. Further derivatization is needed to improve the stability of these inhibitors for the development of therapeutics against Plk1-addicted cancers.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Analytical
Yeo Kyung La, Pethaiah Gunasekaran, Min Su Yim, Gong-Hyeon Lee, Yeon Sil Hwang, Kannan Damodharan, Mi-Hyun Kim, Jeong Kyu Bang, Eun Kyoung Ryu
Summary: In this study, three derivatives targeting PBD for Plk1 were designed by protein-protein interactions, which showed high levels of selectivity and specificity for Plk1 PBD, and were evaluated to inhibit tumor cell proliferation through an apoptotic process during tumor cell division. The investigation of the in vitro and in vivo antitumor effects of these inhibitors demonstrated that one of the new small molecules, 1, is a promising anticancer agent.
JOURNAL OF ANALYTICAL SCIENCE AND TECHNOLOGY
(2023)
Article
Chemistry, Medicinal
Daowei Huang, Jing Zhang, Xiaocong Yang, Xiangduan Tan, Tingting Chai, Lindeng Ma, Bingyang Zhao, Ying Chen, Jixia Yang, Yue Zhang
Summary: A candidate compound based on PLK1-PBD was developed with potent inhibitory and anti-proliferative activities, as well as favorable safety and ADMET properties.
LETTERS IN DRUG DESIGN & DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Femi Olawale, Opeyemi Iwaloye, Olusola Olalekan Elekofehinti
Summary: The over-expression of PLK1 is linked to cancer prognosis, and this study identified potential inhibitors by targeting the NCD and PBD domains of PLK1 through pharmacophore modeling and molecular docking. The hit compounds showed promising inhibitory activity and drug-like properties for further experimental validation.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Multidisciplinary Sciences
Laura J. Bailey, Rebecca Teague, Peter Kolesar, Lewis J. Bainbridge, Howard D. Lindsay, Aidan J. Doherty
Summary: Replication stress and DNA damage can stall replication forks and impede genome synthesis. PrimPol, regulated by PLK1 phosphorylation, plays a crucial role in damage tolerance pathway during S phase to ensure efficient genome duplication and prevent genomic instability.
Article
Biochemistry & Molecular Biology
Hiromasa Yoshioka, Tatsuro Kawamura, Makoto Muroi, Yasumitsu Kondoh, Kaori Honda, Makoto Kawatani, Harumi Aono, Herbert Waldmann, Nobumoto Watanabe, Hiroyuki Osada
Summary: The compound NPD4928 was identified to enhance the sensitivity of various cancer cells to GPX4 inhibitors, potentially having therapeutic potential via the induction of ferroptosis.
ACS CHEMICAL BIOLOGY
(2022)
Article
Oncology
Xiaopan Zou, Yan Liu, Jun Di, Wei Wei, Nobumoto Watanabe, Jiang Li, Xiaomeng Li
Summary: This study found that ZMIZ2 is upregulated in TNBC tissues and is associated with its poor prognosis. ZMIZ2 may promote TNBC progression by promoting the expression of its target genes and affecting the corresponding pathways. ZMIZ2 may serve as a promising target for future TNBC treatments.
CANCER CELL INTERNATIONAL
(2022)
Article
Pharmacology & Pharmacy
Wei Wei, Tingting Cao, Janak L. Pathak, Xintong Liu, Tianjiao Mao, Nobumoto Watanabe, Xiaomeng Li, Manli Zhang, Jiang Li
Summary: This study found that apigenin, as a single active component of herbal extract, can upregulate AQP5 expression in salivary gland cells through activation of the ER alpha signaling pathway, thus treating xerostomia.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Nobuo Cho, Ko Kikuzato, Yushi Futamura, Takeshi Shimizu, Hiroki Hayase, Kikuko Kamisaka, Daisuke Takaya, Hitomi Yuki, Teruki Honma, Mamoru Niikura, Fumie Kobayashi, Nobumoto Watanabe, Hiroyuki Osada, Hiroo Koyama
Summary: This study describes the identification, structure-activity relationships, and biological effects of a new class of antimalarials. Through a cell-based phenotypic approach, a hit compound with significant in vitro activity was identified and further SAR studies led to the discovery of a compound with potent inhibition of parasite growth. The compound showed significant in vivo antimalarial effects in mouse models, and molecular modeling studies suggested its preferential adoption of an active conformer.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biotechnology & Applied Microbiology
Weng Yu Lai, Zhenpei Wong, Chiat Han Chang, Mohd Razip Samian, Nobumoto Watanabe, Aik-Hong Teh, Rahmah Noordin, Eugene Boon Beng Ong
Summary: Leptospirosis is a zoonotic disease caused by pathogenic Leptospira spp., with global implications primarily in tropical countries. This study used the budding yeast model to screen for putative virulence factors (VFs) of L. interrogans, one of the dominant species causing leptospirosis, and identified nine potential VFs in four categories. The study highlights the existence of undiscovered VFs in L. interrogans.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Megumi Aoyama, Kosuke Ishikawa, Shuntaro Nemoto, Hiroyuki Hirano, Nobumoto Watanabe, Hiroyuki Osada, Shinya Watanabe, Kentaro Semba
Summary: This study establishes a system to evaluate the cancer-inhibitory activity of surrounding nontransformed cells and identifies lonidamine and domperidone as compounds that can inhibit the expansion of oncogenic foci. The findings suggest that these compounds suppress the movement of nontransformed cells and promote stress fiber formation, potentially leading to the development of a new type of drug that induces the anticancer activity of surrounding non-transformed cells.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Plant Sciences
Marco Burger, Kaori Honda, Yasumitsu Kondoh, Sharon Hong, Nobumoto Watanabe, Hiroyuki Osada, Joanne Chory
Summary: In Arabidopsis thaliana, the Sigma factor B regulator RsbQ-like family consists of three proteins: the strigolactone receptor DWARF14 (AtD14), the karrikin receptor KARRIKIN INSENSITIVE2 (AtKAI2), and the unknown function protein DWARF14-LIKE2 (AtDLK2). Despite similar protein folds, AtD14 and AtKAI2 have different ligand binding pockets that affect their substrate specificity. The crystal structure of AtDLK2 reveals the smallest ligand binding pocket in this protein family, and a compound that inhibits its enzymatic activity has been identified.
Article
Biochemical Research Methods
Bo Chen, Jiannan Zhou, Tianjiao Mao, Tingting Cao, Shilin Hu, Wenqi Zhang, Xueyang Li, Xiuni Qin, Xintong Liu, Nobumoto Watanabe, Jiang Li
Summary: The study identified new potential therapeutic targets and signaling pathways related to Sjogren's syndrome through experiments on NOD mice models, providing a strategy for clinical treatment of the disease.
BIOLOGICAL PROCEDURES ONLINE
(2022)
Article
Oncology
Bo Chen, Tianjiao Mao, Xiuni Qin, Wenqi Zhang, Nobumoto Watanabe, Jiang Li
Summary: This study identified novel biomarkers affecting the prognosis of DLBCL and identified STAT and KRAS pathways as potential growth regulatory pathways. These findings provide new avenues for the treatment of DLBCL patients.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Shilin Hu, Bo Chen, Jiannan Zhou, Fangqi Liu, Tianjiao Mao, Janak L. Pathak, Nobumoto Watanabe, Jiang Li
Summary: DPSC-Exos have been found to possess anti-inflammatory, anti-oxidative, immunomodulatory, and tissue function restorative abilities, which can potentially restore salivary gland function in Sjogren's syndrome (SS). Both in vitro and in vivo experiments demonstrated that DPSC-Exos could protect salivary gland epithelial cells from SS-induced damage and promote salivary secretion. These findings suggest the therapeutic potential of DPSC-Exos in SS treatment.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Behavioral Sciences
Florence Hui Ping Tan, Nazalan Najimudin, Nobumoto Watanabe, Shaharum Shamsuddin, Ghows Azzam
Summary: Alzheimer's disease (AD) is a common neurodegenerative condition, and the accumulation of amyloid-beta (Aβ) is part of its pathophysiology. The compound p-Coumaric acid (pCA), known for its therapeutic benefits, was found to reduce Aβ fibrillation in vitro and decrease Aβ-induced cell mortality in neuronal cells. In a Drosophila melanogaster model, pCA partially reversed the phenotypic characteristics of AD, increased lifespan, and improved mobility in a sex-dependent manner. These findings suggest that pCA may have therapeutic benefits for AD.
BEHAVIOURAL BRAIN RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Tingting Cao, Jiannan Zhou, Qianwen Liu, Tianjiao Mao, Bo Chen, Qingqing Wu, Lijing Wang, Janak L. Pathak, Nobumoto Watanabe, Jiang Li
Summary: In this study, it was found that elevated levels of IFN-gamma induce ferroptosis in salivary gland epithelial cells (SGEC) in Sjogren's syndrome (SS) through JAK/STAT1 signaling, by inhibiting the function of system Xc(-). Transcriptome analysis revealed differential expression of ferroptosis-related markers in human and mouse salivary glands of SS, with upregulation of IFN-gamma and downregulation of GPX4 and AQP5. Manipulating ferroptosis or IFN-gamma signaling can alleviate or aggravate SS symptoms in mouse models.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Review
Materials Science, Biomaterials
Jiannan Zhou, Janak Lal Pathak, Qianwen Liu, Shilin Hu, Tingting Cao, Nobumoto Watanabe, Yongliang Huo, Jiang Li
Summary: Sjogren's syndrome is an autoimmune disease that primarily affects middle-aged and older women, leading to dry mucosal surfaces. It is caused by dysfunction of secretory glands, such as the oral cavity, eyeballs, and pharynx. Lymphocyte infiltration and epithelial cell destruction triggered by Ro/SSA and La/SSB autoantibodies are the pathological characteristics of the syndrome. The exact pathogenesis is still unclear, but evidence suggests that epithelial cell death and subsequent dysfunction of salivary glands are the main causes of xerostomia.
Article
Oncology
Xintong Liu, Emiko Sanada, Jiang Li, Xiaomeng Li, Hiroyuki Osada, Nobumoto Watanabe
Summary: Beta-transducin repeat-containing protein (beta-TrCP) is an F-box protein subunit of the E3 Skp1-Cullin-F box (SCF) ubiquitin-ligase complex. We developed a high-throughput screening system to identify small molecule ligands of beta-TrCP, and obtained several hit compounds that effectively inhibited beta-TrCP in cells. In silico analysis revealed the important moieties of these hit compounds and their hydrogen bonding with beta-TrCP.
Article
Oncology
Ziyu Liu, Akiko Okano, Emiko Sanada, Yushi Futamura, Toshihiko Nogawa, Kosuke Ishikawa, Kentaro Semba, Jiang Li, Xiaomeng Li, Hiroyuki Osada, Nobumoto Watanabe
Summary: In this study, a screening strategy was established to identify natural products as potential c-Myc inhibitors. A microbial extract from Streptomyces sp. RK19-A0402 was found to strongly inhibit c-Myc transcriptional activity. Compounds in the extract showed structural similarities to cytovaricin and oligomycin A, and inhibited mitochondrial complex V, leading to mitochondrial dysfunction and the production of reactive oxygen species (ROS). The ROS then activated GSK3α/β to phosphorylate c-Myc, promoting its ubiquitination.
