Article
Biochemistry & Molecular Biology
Yue Zhou, Ryota Oki, Akihiro Tanaka, Leixin Song, Atsushi Takashima, Naru Hamada, Satoru Yokoyama, Seiji Yano, Hiroaki Sakurai
Summary: Under cellular stress conditions, non-canonical EphA2 activation occurs through the p38-MK2-RSK pathway and promotes glioblastoma cell migration.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Kimberly A. Casalvieri, Christopher J. Matheson, Becka M. Warfield, Donald S. Backos, Philip Reigan
Summary: The study developed a series of compounds to inhibit cellular RSK2 activity by replacing the pteridinone ring of BI-D1870, with some compounds uncoupling cellular RSK2 inhibition from potent cytotoxicity in the MOLM-13 AML cell line. This suggests the potential for improved RSK potency and selectivity by further examining substituents extending from the ATP- to the substrate-binding site.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Lucia Suarez-Lopez, Bing Shui, Douglas K. Brubaker, Marza Hill, Alexander Bergendorf, Paul S. Changelian, Aisha Laguna, Alina Starchenko, Douglas A. Lauffenburger, Kevin M. Haigis
Summary: Inflammatory bowel diseases (IBDs) are genetically complex and exhibit significant inter-patient heterogeneity. Mouse models of IBD show varied responses to MK2 inhibition, with MK2 suppressing inflammation by targeting inflammatory cells. Using a computational approach, researchers identified IBD patient subgroups predicted to respond to MK2 inhibition, which can aid in identifying which patients will benefit from new therapies.
Article
Chemistry, Medicinal
Yuan Yuan, Junpeng Xu, Lei Jiang, Kangjie Yu, Yuanyuan Ge, Mingyang Li, Huan He, Qiqi Niu, Xiayu Shi, Linni Fan, Zhuo Chen, Zhenjiang Zhao, Shiliang Li, Yufang Xu, Zhe Wang, Honglin Li
Summary: A series of novel and potent RSK4 inhibitors were designed and synthesized in this study, with compound 14f showing strong inhibitory activity on ESCC cell proliferation and invasion both in vitro and in vivo. It selectively inhibited the phosphorylation of RSK4 downstream substrates in ESCC cells, with little effect on RSK1-3 substrates. The promising efficacy of 14f in suppressing tumor growth and lack of observed toxicity suggests it as a potential RSK4-targeting agent for ESCC treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Adam L. Poti, Laura Denes, Kinga Papp, Csaba Bato, Zoltan Banoczi, Attila Remenyi, Anita Alexa
Summary: Protein kinases are essential for cell signaling and have been targeted for therapeutic purposes for many years. Inhibiting kinase activity or interfering with kinase docking can be alternative strategies for controlling kinases. The development of phosphorylation-assisted luciferase complementation (PhALC) sensors allows for the quantitative analysis of kinase activity or kinase docking, making it a useful tool in research and high-throughput screening.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Endocrinology & Metabolism
Deborah A. Lannigan
Summary: This review focuses on the coordination between ERK1/2-RSK2 and estrogen signaling through ERα, and their interrelationships at the levels of transcription, translation, and posttranslational modification. Understanding how they cooperate in homeostasis and disease may lead to new therapeutic approaches for estrogen-dependent disorders.
Article
Cell Biology
Won Seok Yang, Maisel J. Caliva, Vedbar S. Khadka, Maarit Tiirikainen, Michelle L. Matter, Youping Deng, Joe W. Ramos
Summary: The 90 kDa ribosomal S6 kinases (RSKs), comprising four isoforms, play important roles in the regulation of migration, invasion, proliferation, survival, and transcription in various types of cancer. In this study, the specific functions of RSK1 and RSK2 in gene regulation were explored by comparing their knockout cells using microarray analysis. The results reveal distinct mRNA expression patterns and specific functions of RSK1 and RSK2 in different pathways. These findings provide valuable insights into the transcriptional regulation mediated by these closely related isoforms.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Eric B. Wright, Shinji Fukuda, Mingzong Li, Yu Li, George A. O'Doherty, Deborah A. Lannigan
Summary: The study identified a natural product, SL0101, that binds specifically to RSK1/2 by inducing conformational rearrangement, but not to RSK3/4 due to a single amino acid difference. Kinetic analysis revealed that regions outside of the N-terminal kinase domain also contribute to stable inhibitor binding towards RSK2. Additionally, a modification on SL0101 was discovered to form a highly stable inhibitor complex with RSK2, suggesting potential for identifying RSK2-specific inhibitors.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemical Research Methods
Yuzhen Dan, Nevenka Radic, Marina Gay, Adria Fernandez-Torras, Gianluca Arauz, Marta Vilaseca, Patrick Aloy, Begona Canos, Angel R. Nebreda
Summary: p38α is a protein kinase that regulates cellular responses to various stresses. We identified 35 proteins and 82 phosphoproteins that are modulated by p38α and highlighted the involvement of protein kinases MK2 and mTOR in p38α-regulated signaling networks. Our results provide valuable information on p38α-dependent phosphorylation events in cancer cells and reveal a mechanism by which p38α regulates cell adhesion.
MOLECULAR & CELLULAR PROTEOMICS
(2023)
Review
Biochemistry & Molecular Biology
Minyoung Youn, Jesus Omar Gomez, Kailen Mark, Kathleen M. Sakamoto
Summary: RSKs are a group of serine/threonine kinases functioning downstream of the Ras/Raf/MEK/ERK signaling pathway, phosphorylating various targets to regulate cellular processes. In hematological malignancies like AML, overexpression and aberrant activation of RSK isoforms may lead to poor outcomes and chemotherapy resistance.
Article
Pharmacology & Pharmacy
Hannah A. Blair
Summary: Belumosudil, a ROCK inhibitor developed by Kadmon Pharmaceuticals, has received its first approval in the USA for the treatment of cGVHD. Regulatory reviews are underway in other countries, and clinical development for systemic sclerosis is ongoing in the USA.
Article
Multidisciplinary Sciences
Jinxin Li, Huimin Sun, Meiling Fu, Zeyuan Zheng, Chunlan Xu, Kunao Yang, Yankuo Liu, Zuodong Xuan, Yang Bai, Jianzhong Zheng, Yue Zhao, Zhiyuan Shi, Chen Shao
Summary: This study demonstrates that high expression of TOPK in RCC promotes PD-L1 expression by activating ERK2 and TGF-beta/Smad pathways. TOPK is also shown to inhibit CD8(+) T cell infiltration and function, promoting immune escape in RCC. Inhibition of TOPK enhances CD8(+) T cell infiltration, activation, anti-PD-L1 therapeutic efficacy, and synergistically enhances anti-RCC immune response.
Article
Chemistry, Medicinal
Seungbeom Lee, Jisu Kim, Jeyun Jo, Jae Won Chang, Jaehoon Sim, Hwayoung Yun
Summary: Bivalent kinase inhibitors have emerged as a promising approach for targeting specific kinases with enhanced selectivity and affinity through increased interactions with target enzymes. Recent developments have led to the creation of bivalent compounds with high kinase affinity, biological and chemical stability in vivo, offering significant potential for therapeutic applications. This review provides a comprehensive overview of hetero-bivalent kinase inhibitors and discusses their advantages, limitations, and future prospects compared to monovalent kinase inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biotechnology & Applied Microbiology
Hannah I. Ghasemi, Julien Bacal, Amanda C. Yoon, Katherine U. Tavasoli, Carmen Cruz, Jonathan T. Vu, Brooke M. Gardner, Chris D. Richardson
Summary: The efficiency of gene editing via homology-directed repair (HDR) can be enhanced by covalently modifying the template DNA to form interstrand crosslinks. These crosslinked templates (xHDRTs) significantly increase Cas9-mediated editing efficiencies in various cell types. The increased editing from xHDRTs is dependent on events occurring on the template molecule and requires the ATR kinase and components of the Fanconi anemia pathway.
NATURE BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
Derek K. Cheng, Tobiloba E. Oni, Jennifer S. Thalappillil, Youngkyu Park, Hsiu-Chi Ting, Brinda Alagesan, Nadia V. Prasad, Kenneth Addison, Keith D. Rivera, Darryl J. Pappin, Linda Van Aelst, David A. Tuveson
Summary: The study identified protein interactors of active KRAS in PDAC cells using proximity labeling, revealing that RSK1 selectively interacts with membrane-bound KRASG12D through NF1 and SPRED2. It was found that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS in PDAC, highlighting the role of WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
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)