Article
Biochemistry & Molecular Biology
Igor A. Schepetkin, Oleksander S. Karpenko, Anastasia R. Kovrizhina, Liliya N. Kirpotina, Andrei I. Khlebnikov, Stepan I. Chekal, Alevtyna V. Radudik, Maryna O. Shybinska, Mark T. Quinn
Summary: The JNK family, including JNK1-3 proteins, regulates various physiological processes. The study aimed to find JNK inhibitors with high selectivity for JNK3. 26 new tryptanthrin-6-oxime analogs were synthesized and evaluated, and compounds 4d and 4e showed high selectivity for JNK3 and inhibited inflammatory responses. The results suggest the potential for developing anti-inflammatory drugs with selectivity for JNK3.
Article
Multidisciplinary Sciences
Jiao Luo, Xiujun Tan, Ling Ye, Chenglin Wang
Summary: The study reveals that the JNK signaling pathway plays a positive role in the formation of dental papilla cell polarity, as indicated by the up-regulation of polarity-related genes and rescue effects of RhoA Q63L mutant. JNK activation is linked to polarization, migration, and differentiation of dental papilla cells, highlighting its importance in tooth development.
Article
Biochemistry & Molecular Biology
Serhii A. Liakhov, Igor A. Schepetkin, Olexander S. Karpenko, Hanna Duma, Nadiia M. Haidarzhy, Liliya N. Kirpotina, Anastasia R. Kovrizhina, Andrei Khlebnikov, Irina Y. Bagryanskaya, Mark T. Quinn
Summary: In this study, 13 derivatives of a JNK inhibitor were synthesized, with 8 compounds showing submicromolar binding affinity for at least one JNK isoform, and most of them exhibiting anti-inflammatory effects. Selected compounds also directly confirmed JNK inhibition, indicating their potential as lead compounds for anti-inflammatory drug development.
Article
Biochemistry & Molecular Biology
Zhelong Nie, Xiaoli Xia, Yang Zhao, Sheng Zhang, Yanwei Zhang, Junhui Wang
Summary: The study demonstrated that IQ-1S significantly reduced mortality and lung inflammation in sepsis mice by inhibiting inflammatory cytokine levels and suppressing M1 macrophage polarization. Furthermore, IQ-1S effectively inhibited the activation of the JNK signaling pathway and reduced the phosphorylation level of JNK2 in sepsis mice, ultimately protecting the mice against LPS-induced sepsis.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Agriculture, Multidisciplinary
Wan Wang, Cong Xu, Xuan Zhou, Le Zhang, Liya Gu, Zhijing Liu, Jiage Ma, Juncai Hou, Zhanmei Jiang
Summary: This study explored the effects of probiotics and prebiotics in alleviating neurodegenerative diseases. The combination of Lactobacillus plantarum and galactooligosaccharides was found to reduce oxidative stress and increase levels of nuclear factor erythroid 2-related factor 2 in the brain. Additionally, the combination regulated the gut microbiota metabolite butyrate, which inhibited expression of p-JNK, downregulated pro-apoptotic proteins and inflammatory mediators, and upregulated synaptic protein expression. This suggests that Lactobacillus plantarum combined with galactooligosaccharides may have potential in alleviating neurodegeneration and memory impairment induced by D-galactose.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Oncology
Keiko Tanimura, Tadaaki Yamada, Mano Horinaka, Yuki Katayama, Sarina Fukui, Kenji Morimoto, Takayuki Nakano, Shinsaku Tokuda, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Kazue Yoneda, Seiji Yano, Toshiyuki Sakai, Koichi Takayama
Summary: Through activation of the JNK/c-Jun signaling, novel adaptive resistance has been identified as a key factor leading to failure of ALK-TKIs treatment, suggesting that combination therapy targeting JNK and ALK-TKIs may significantly delay regrowth of lung cancer cells and potentially improve patient outcomes.
Article
Biochemistry & Molecular Biology
Anna A. Zhdankina, Dmitry I. Tikhonov, Sergey V. Logvinov, Mark B. Plotnikov, Andrei I. Khlebnikov, Nataliya G. Kolosova
Summary: Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. JNK inhibitor IQ-1S shows potential in preventing and treating AMD, as it improves histological abnormalities associated with retinopathy in the OXYS rat model, including improved blood circulation, increased functional activity of the retinal pigment epithelium, reduced VEGF expression, and increased PEDF expression.
Article
Oncology
Milad Soleimani, Alexander Somma, Tamer Kaoud, Ria Goyal, Jorge Bustamante, Dennis C. Wylie, Nisha Holay, Agnieszka Looney, Uma Giri, Todd Triplett, Kevin Dalby, Jeanne Kowalski, S. Gail Eckhardt, Carla Van Den Berg
Summary: JNK-IN-8, a covalent JNK inhibitor, suppresses the growth of triple-negative breast cancer (TNBC) by activating TFEB/TFE3 and inducing lysosome biogenesis and autophagy via mTOR inhibition independently of JNK.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Rahat Ullah, Muhammad Ikram, Tae Ju Park, Riaz Ahmad, Kamran Saeed, Sayed Ibrar Alam, Inayat Ur Rehman, Amjad Khan, Ibrahim Khan, Min Gi Jo, Myeong Ok Kim
Summary: The study demonstrated that vanillic acid (V.A) exhibits neuroprotective effects against lipopolysaccharides (LPS)-induced neuroinflammatory processes by inhibiting the JNK signaling pathway mediated by LPS/RAGE. Furthermore, V.A was found to attenuate synaptic loss and improve memory performance induced by LPS, suggesting its potential as a neuroprotective and neurotherapeutic agent for various neurological disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Yao-Lei Zhang, Xu-Dong Wen, Xin Guo, Shang-Qing Huang, Ting-Ting Wang, Pei-Ting Zhou, Wei Li, Long-Fu Zhou, Yong-He Hu
Summary: Low expression of progesterone and PGR are significantly associated with poor prognosis of CRC. Progesterone suppresses CRC cell proliferation by arresting the cell cycle and inducing apoptosis. Progesterone up-regulates GADD45 alpha to activate the JNK pathway, inhibiting the malignant progression of CRC.
Article
Cell Biology
Bahareh Tabanifar, Anbalagan Moorthy, Heng Hang Tsai, Srinivasaraghavan Kannan, Chandra S. Verma, Kanaga Sabapathy
Summary: This study reveals a mechanism of cell death mediated by JNK, involving the degradation of the anti-apoptotic protein APE1. Upon exposure to genotoxic stress, JNK interacts with APE1, leading to its ubiquitination and degradation, which ultimately triggers cell death.
Review
Biochemistry & Molecular Biology
Hyunwook Cho, Jung-Mi Hah
Summary: JNK3 plays a crucial role in neurodegenerative diseases, and this study summarizes the research on JNK3 inhibitors, focusing on structural and docking insights.
Article
Biochemistry & Molecular Biology
Masanori Itakura, Takeya Kubo, Akihiro Kaneshige, Hidemitsu Nakajima
Summary: GAPDH interacts with JNK and promotes its activation under oxidative stress, which is dependent on the oxidation of the active-site cysteine (Cys152) in GAPDH. Inhibition of GAPDH expression reduces JNK activation and attenuates the translocation of Bax protein to mitochondria. Therefore, GAPDH plays a significant role in the JNK signaling pathway under oxidative stress.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Hewen Qian, Yuanqing Ding, Xingyu Deng, Weiwei Huang, Zhenzhen Li, Fengling Liu, Jie Zhang, Lihui Wang, Junping Liu, Yaxia Yuan, Shurong Hou, Xiabin Chen, Lei Ma
Summary: In this study, a strategy based on computational prediction of synthetic feasibility and fragment-based molecule generation was used to design JNK1 inhibitors. Several potent JNK1 inhibitors were discovered, with compound C6 exhibiting comparable activity to the clinical candidate CC-90001. Compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. These findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Hipolito Nicolas Cuesta-Hernandez, Julia Contreras, Pablo Soriano-Maldonado, Jana Sanchez-Wandelmer, Wayland Yeung, Ana Martin-Hurtado, Ines G. Munoz, Natarajan Kannan, Marta Llimargas, Javier Munoz, Ivan Plaza-Menacho
Summary: This study identifies the C-terminal tyrosine 530 as the autophosphorylation site in protein kinases, which is controlled by the activation-loop tyrosine 419. The phosphorylation switch between these two sites regulates the autophosphorylation of tyrosine 530, enzyme specificity, and non-catalytic function of c-Src as a substrate. The interaction between the activation and C-terminal segments is crucial for the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)