Review
Immunology
Kimia Ghasemi, Kosar Ghasemi
Summary: Chemokines and their receptors play crucial roles in immune responses. CXCR4, a GPCR, interacts with SDF-1 to regulate multiple signaling pathways and has potential therapeutic value in cancer treatment. MSX-122, an orally available CXCR4 antagonist, shows promising anti-cancer properties, especially in treating metastatic cancers.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Hee-Kyung Park, Lan Phuong Nguyen, Thai Uy Nguyen, Minyeong Cho, Huong Thi Nguyen, Sunghoon Hurh, Hong-Rae Kim, Jae Young Seong, Cheol Soon Lee, Byung-Joo Ham, Jong-Ik Hwang
Summary: CXCL12 is an essential chemokine for organ development and homeostasis, and its receptor CXCR4 is widely expressed on target cells. Multiple splice variants of CXCR4 have been identified, and these variants have different expression patterns and cellular functions. The variants may also interact with each other during cellular responses to CXCL12. Therefore, further investigation of the functional roles of CXCR4 variants could contribute to the development of novel drug interventions.
Article
Chemistry, Medicinal
Renato Ferreira de Freitas, Yanli Liu, Magdalena M. Szewczyk, Naimee Mehta, Fengling Li, David McLeod, Carlos Zepeda-Velazquez, David Dilworth, Ronan P. Hanley, Elisa Gibson, Peter J. Brown, Rima Al-Awar, Lindsey James, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy, Jinrong Min, Masoud Vedadi, Matthieu Schapira, Abdellah Allali-Hassani
Summary: This study identified the first antagonist that blocks the interaction between NSD2 and H3K36me2, providing a potential new approach for targeting NSD2 and further understanding its cellular function.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Alexander Kroll, Sahasra Ranjan, Martin K. M. Engqvist, Martin J. Lercher
Summary: For most proteins annotated as enzymes, it is unknown which primary and/or secondary reactions they catalyze. Machine learning predictions could provide an efficient alternative, but are hampered by a lack of information regarding enzyme non-substrates, as available training data comprises mainly positive examples. Here, we present ESP, a general machine-learning model for the prediction of enzyme-substrate pairs with an accuracy of over 91% on independent and diverse test data.
NATURE COMMUNICATIONS
(2023)
Review
Pharmacology & Pharmacy
Hossein Hemmatazad, Martin D. Berger
Summary: CCR5 plays a crucial role in cancer progression by modulating immune response and promoting tumor cell proliferation and invasion. CCR5 antagonists show promising efficacy in preclinical tumor models, indicating the potential of CCR5 as a therapeutic target for cancer beyond immune-checkpoint inhibitors.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Chemistry, Medicinal
Sebastian Dekkers, Birgit Caspar, Joelle Goulding, Nicholas D. Kindon, Laura E. Kilpatrick, Leigh A. Stoddart, Stephen J. Briddon, Barrie Kellam, Stephen J. Hill, Michael J. Stocks
Summary: In this study, fluorescent probes based on previously reported small-molecule antagonists were designed and synthesized using classic medicinal chemistry approaches to investigate the pharmacology and cellular distribution of the CXCR4 receptor. Three distinct chemical classes of fluorescent probes were developed and shown to specifically bind to the CXCR4 receptor in a fluorescence-based NanoBRET binding assay (pKD ranging 6.6-7.1). These probes were also used in competition binding experiments and confocal microscopy to further explore the pharmacology and cellular distribution of CXCR4.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Immunology
Teizo Yoshimura, Chunning Li, Yuze Wang, Akihiro Matsukawa
Summary: Breast cancer is a common cancer worldwide, and metastasis is the main cause of cancer-related death. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was identified as a chemotactic factor for monocytes, and its role in cancer development and progression was investigated. Studies showed positive correlations between MCP-1 production in tumors and TAM infiltration, as well as cancer progression. MCP-1 was found to promote breast cancer metastasis to the lung and brain, but not bone. The mechanisms of MCP-1 production in the breast cancer microenvironment were also reported.
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Yaxin Li, Cody M. Orahoske, Werner J. Geldenhuys, Asmita Bhattarai, Abboud Sabbagh, Viharika Bobba, Fatma M. Salem, Wenjing Zhang, Girish C. Shukla, Justin D. Lathia, Bingcheng Wang, Bin Su
Summary: Compound I, an HSP27 inhibitor, effectively induces AR degradation in GBM cells via the proteasomal pathway, selectively inhibiting the growth of AR-overexpressed GBM cells. These findings suggest that targeting HSP27 to induce AR degradation in GBM shows promise as a novel treatment approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biology
Astrid S. Jorgensen, Viktorija Daugvilaite, Katia De Filippo, Christian Berg, Masa Mavri, Tau Benned-Jensen, Goda Juzenaite, Gertrud Hjorto, Sara Rankin, Jon Vabeno, Mette M. Rosenkilde
Summary: Plerixafor exhibits biased action by reversing the CXCL12 gradient across the bone marrow endothelium and showing superior therapeutic effect in HSC mobilization. In contrast, AMD11070, despite having superior antagonism, does not perform as effectively in HSC mobilization in vivo.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Margaux Billen, Dominique Schols, Peter Verwilst
Summary: Since the discovery of the first biologically active chemokines in the late 1980s, these messenger proteins and their receptors have become targets for drug discovery efforts. Recent research has focused on a highly druggable, intracellular, allosteric binding site that partially overlaps with the G protein binding site, and the development of antagonists.
CHEMICAL COMMUNICATIONS
(2022)
Article
Biology
Valentina Poltavets, Jessica W. Faulkner, Deepak Dhatrak, Robert J. Whitfield, Shaun R. McColl, Marina Kochetkova
Summary: The CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signaling responses in invasive breast cancer cell lines and primary mammary human tumor cells. The presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumors directly correlates with the severity of the disease, and their forced heterodimerization leads to the acquisition of invasive phenotype in non-metastatic breast cancer cells. These findings establish the CXCR4-CCR7 receptor complex as a new functional unit responsible for the acquisition of breast cancer cell metastatic phenotype and a potential novel biomarker for invasive mammary tumors.
Article
Multidisciplinary Sciences
Wenwei Lin, Andrew D. Huber, Shyaron Poudel, Yongtao Li, Jayaraman Seetharaman, Darcie J. Miller, Taosheng Chen
Summary: The promiscuity of ligand-binding in detoxification systems is beneficial for body protection but a challenge for drug development. Through X-ray crystallography, we found that expanding the ligand-binding pocket of the PXR receptor can enhance binding affinity. However, this expansion is an unfavorable event, and engineering ligands to avoid clashes with the receptor can reduce safety liabilities. Therefore, engineering the ligand-binding pocket of PXR can potentially improve drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Endocrinology & Metabolism
Soudeh Ghafouri-Fard, Kasra Honarmand, Mohammad Taheri
Summary: Multiple sclerosis (MS) is considered to be a chronic inflammatory disorder of the central nervous system caused by abnormal immune responses. Chemokines play an important role in the pathogenesis of MS, with several members of this family being dysregulated in MS patients' peripheral blood, cerebrospinal fluid, or CNS lesions. Studies in animal models have shown the critical roles of chemokines in the pathophysiology of MS.
METABOLIC BRAIN DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Kiyoshi Takatsu
Summary: The mammalian immune system is divided into innate and acquired immunity. Recent trends in immunology have shifted from a focus on acquired immunity, represented by peptide recognition by T-cell receptor, to innate immunity, represented by the recognition of pathogen-derived molecular patterns including lipid and carbohydrate. This article focuses on recent hotspots in inflammation research, particularly inflammasome and immunometabolism, with an emphasis on small molecule inhibitors of NLRP3 inflammasome activation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Srilatha Sakamuru, Jinghua Zhao, Menghang Xia, Huixiao Hong, Anton Simeonov, Iosif Vaisman, Ruili Huang
Summary: Novel computational models were developed to predict the activity of opioid receptors based on chemical structures, successfully identifying new active compounds. Experimental validation showed that the best performing model, using the random forest classifier, achieved hit rates ranging from 2.3% to 15.8%, enriching hit rates by >= 2-fold compared to the original assay.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)