We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
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Front Immunol
December 2024
Department of Medicine, Harvard Medical School, Boston, MA, United States.
The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained.
View Article and Find Full Text PDFDrug Discov Today
December 2024
Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. Electronic address:
Spleen tyrosine kinase (SYK) is a crucial non-receptor tyrosine kinase involved in signaling pathways that regulate various cellular processes. It is primarily expressed in hematopoietic cells and myeloid cells, which are crucial for B-cell development, maturation and antibody production, and it is a key therapeutic target for autoimmune and allergic diseases. Overexpression of SYK is also associated with cancer and cardiovascular, cerebrovascular and neurodegenerative diseases, contributing to their initiation and progression.
View Article and Find Full Text PDFJ Neuroinflammation
December 2024
Department of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, 730000, China.
Background: Chronic migraine (CM) is a serious neurological disorder. Central sensitization is one of the important pathophysiological mechanisms underlying CM, and microglia-induced neuroinflammation conduces to central sensitization. Triggering receptor expressed on myeloid cells 2 (TREM2) is presented solely in microglia residing within the central nervous system and plays a key role in neuroinflammation.
View Article and Find Full Text PDFJ Neuroinflammation
November 2024
Department of Neurology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, 710038, China.
Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-triggered central nervous system (CNS) demyelinating disease that primarily affects the spinal cord, optic nerves and brainstem. Among the first responders to CNS injury, microglia are prominent players that drive NMOSD lesion formation. However, the key molecular switches controlling the detrimental activity of microglia in NMOSD are poorly understood.
View Article and Find Full Text PDFMicrobiol Spectr
January 2025
BioMEMS Resource Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Unlabelled: Neutrophils communicate with one another and amplify their destructive power through swarming, a collective process that synchronizes the activities of multiple neutrophils against one target. The sequence of activities contributing to swarming against clusters of fungi has been recently uncovered. However, the molecular signals controlling the neutrophils' activities during the swarming process are just emerging.
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