Review
Chemistry, Medicinal
Tiandi Ding, Ying Zhi, Weilin Xie, Qingqiang Yao, Bo Liu
Summary: Sphingosine kinases are lipid kinases that phosphorylate sphingosine to sphingosine-1-phosphate, playing a role in regulating biological processes; targeting their signaling pathway is a potential treatment strategy for various pathophysiological conditions.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
ShaSha Wang, Yidan Huo, Jinmiao Zhang, Longfei Li, Fei Cao, Yali Song, Yajing Zhang, Kan Yang
Summary: Targeting sphingosine kinase 2 (SphK2) has been identified as a novel strategy for cancer treatment. However, there is a lack of potent and selective SphK2 inhibitors. In this study, a series of novel SphK2 inhibitors were designed, synthesized, and screened, with compound 12e showing the strongest inhibitory activity. Molecular dynamics simulations were performed to analyze the detailed interactions between SphK2 and its inhibitors. In addition, 12e exhibited anti-proliferative activity in various cancer cells and inhibited the migration of MCF-7 breast cancer cells.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Mireia Sueca-Comes, Elena Cristina Rusu, Anna M. Grabowska, David O. Bates
Summary: The number of cancer drugs is increasing, but most research is still focused on a small subset of well-studied targets, with limited investigations into poorly studied kinases.
PHARMACOLOGICAL REVIEWS
(2022)
Review
Biochemistry & Molecular Biology
Joanna A. Motyl, Joanna B. Strosznajder, Agnieszka Wencel, Robert P. Strosznajder
Summary: Molecular studies suggest that Parkinson's disease is a protein conformational disease involving the spread of alpha-synuclein pathology along the neuraxis. Pathogenic forms of alpha-synuclein induce oxidative stress, neuroinflammation, and protein alterations in neighboring cells, leading to increased toxicity and neurodegeneration. Maintaining homeostasis between bioactive sphingolipids is crucial in cell defense against oxidative stress, with a focus on sphingosine kinases and sphingosine-1-phosphate signaling as potential pharmacological targets for neurological diseases like PD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Yuqing Wu, Yongjie Liu, Erich Gulbins, Heike Grassme
Summary: Sphingolipids play crucial roles in regulating pathobiological processes such as cancer, inflammation, and infectious diseases. Unlike ceramide which promotes microbial infections, sphingosine has bactericidal effects and is an important natural defense component against bacterial pathogens in the respiratory tract. Recent studies suggest that the bactericidal effect of sphingosine may be due to bacterial membrane permeabilization and subsequent bacterial death.
Article
Virology
Rachel S. Resop, Alberto Bosque
Summary: Inhibition of SPHK can reduce HIV-1 transmission between CD4 T cells and decrease susceptibility to infection, which may serve as a basis for developing strategies to prevent HIV-1 infection.
JOURNAL OF VIROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Magdalena Wujak, Anna Kozakiewicz, Anna Ciarkowska, Joanna I. Loch, Magdalena Barwiolek, Zuzanna Sokolowska, Marcin Budny, Andrzej Wojtczak
Summary: Statins, known for their cholesterol-lowering effects, have also shown anti-cancer and cardio- and neuro-protective properties. Research on interactions between statins and human proteins provides insight into their pleiotropic effects and adverse reactions. In this study, statins were found to inhibit human adenylate kinase isoenzyme 1 (hAK1) in a noncompetitive manner, suggesting potential for the development of new modulators for AK inhibition.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Molly Congdon, Russell G. Fritzemeier, Yugesh Kharel, Anne M. Brown, Vlad Serbulea, David R. Bevan, Kevin R. Lynch, Webster L. Santos
Summary: Elevated levels of Sphingosine 1-phosphate (S1P) and increased expression of Sphingosine kinase iso-forms (SphK1 and SphK2) are associated with various disease states. The development of selective inhibitors for SphK1 and SphK2 has become a focus of drug discovery, with studies focusing on optimizing binding in the SphK2 substrate binding site. The identification of indole-based compounds with 1,5-disubstitution as potent inhibitors highlights the potential for targeting SphK2 with improved potency and selectivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Agnieszka Dreas, Katarzyna Kucwaj-Brysz, Karolina Pyziak, Urszula Kulesza, Ewelina Wincza, Charles-Henry Fabritius, Kinga Michalik, Ewelina Gabor-Worwa, Aniela Golas, Mariusz Milik, Magdalena Masiejczyk, Eliza Majewska, Kazimiera Pysniak, Urszula Wojcik-Trechcinska, Zuzanna Sandowska-Markiewicz, Krzysztof Brzozka, Jerzy Ostrowski, Tomasz Rzymski, Michal Mikula
Summary: The study suggests that inhibition of the MNKs/eIF4E pathway can potentially treat cancer and inflammatory diseases. Compounds 24 and 26, selective and metabolically stable MNK1/2 inhibitors, effectively reduce the phosphorylation levels of eIF4E in pathological conditions, leading to improved survival rates and reduced proinflammatory cytokine levels in mice models.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Skye Montoya, Deborah Soong, Nina Nguyen, Maurizio Affer, Sailasya P. Munamarty, Justin Taylor
Summary: Development of targeted therapies has provided nonchemotherapeutic options for patients, with small molecule kinase inhibitors being a key focus. However, resistance to these therapies may develop, necessitating multiple lines of treatment. Combinations of therapies targeting complimentary pathways may be more effective in overcoming drug resistance.
Article
Pharmacology & Pharmacy
Yajing Ji, Erika M. Lisabeth, Richard R. Neubig
Summary: Pulmonary arterial hypertension (PAH) is a serious disease with poor prognosis, where transforming growth factor beta (TGF-beta) and sphingosine1-phosphate (S1P) signaling pathways are involved in regulating smooth muscle gene expression through downstream signaling molecules. Understanding this mechanism may provide potential therapeutic targets for the treatment of PAH.
MOLECULAR PHARMACOLOGY
(2021)
Article
Oncology
Stefan Gerstenecker, Lisa Haarer, Martin Schroder, Mark Kudolo, Martin P. Schwalm, Valentin Wydra, Ricardo A. M. Serafim, Apirat Chaikuad, Stefan Knapp, Stefan Laufer, Matthias Gehringer
Summary: S6K1 and S6K2 are two human p70 ribosomal S6 kinases associated with various cellular processes and pathologies, particularly cancer. While S6K1 has been well studied and selectively targeted by inhibitors, S6K2 has been neglected despite potential as an anticancer target. By utilizing a unique cysteine residue in S6K2, a highly selective inhibitor was developed, paving the way for specific S6K2 signaling studies.
Article
Biochemistry & Molecular Biology
Karen T. Elvers, Magdalena Lipka-Lloyd, Rebecca C. Trueman, Benjamin D. Bax, Youcef Mehellou
Summary: The research focuses on the mechanism by which SPAK and OSR1 kinases regulate the function of ion co-transporters through phosphorylation, and the potential strategy of inhibiting them by inhibiting their binding with WNK kinases. Crystal structure studies revealed a highly conserved primary pocket and a flexible secondary pocket. Additionally, the affinity of CCT domains to short peptides derived from WNK4 and NKCC1 was evaluated using a biophysical approach.
Article
Pharmacology & Pharmacy
Vijay Kanoje, Dilip Pandey, Akshaya Wagh, Sukanya Patra, Ajit Kumar Marisetti, Madhusudhan Reddy, Charudatt Samant, Nilesh Mahajan, Milind Gholve, Sudeep Sabde, Sneha Trivedi, Trupti Bhankhede, Vinod Patil, Prashant Nigade, Dipak Modi, Maneesh Mehta, Prajakta Ahirrao, Swathi Tota, Bidyut Nanda, Shashikant Pawar, Anuradha Polawar, Kaustubh Tamane, Sandip Kuldharan, Gururaj Vishwase, Nirmal Jana, Sachin J. Mahangare, Prashant Vidhate, Dipak Lagad, Jayasagar Gundu, Samiron Phukan, Manojkumar Shukla, Lakshmi Narasimham, Kumar V. S. Nemmani, Mandar Bhonde, Sharad Sharma, Rajender K. Kamboj, Venkata P. Palle
Summary: This study describes the in vitro and in vivo activity and drug-like properties of the PI3K delta specific inhibitor LL-00071210 in rheumatoid arthritis models. LL-00071210 shows excellent selectivity and stability, demonstrating potential as a clinical drug for the treatment of autoimmune diseases.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Immunology
Tong Li, Xianjing Yang, Juan Zhu, Ying Liu, Xiaobao Jin, Gong Chen, Lianbao Ye
Summary: JAK kinase family includes four members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with STAT signal transmitters and activators of subscription. This pathway is involved in various immune, inflammatory, and tumor diseases. JAK inhibitors, including pan-JAK inhibitors and selective JAK inhibitors, block the signal transduction of the JAK-STAT pathway and show potential in disease treatment. This review provides an overview of the current application status and advances of JAK inhibitors, as well as the structure-activity relationship, aiming to guide the development of novel JAK inhibitors.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)