Recognition of some of the limitations of target-based drug discovery has recently led to the renaissance of a more holistic approach in which complex biological systems are investigated for phenotypic changes upon exposure to small molecules. The subsequent identification of the molecular targets that underlie an observed phenotypic response--termed target deconvolution--is an important aspect of current drug discovery, as knowledge of the molecular targets will greatly aid drug development. Here, the broad panel of experimental strategies that can be applied to target deconvolution is critically reviewed.
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J Med Chem
January 2025
Experimental Drug Development Centre, Chromos, Agency for Science, Technology and Research, 10 Biopolis Road, #05-01, Singapore 138670.
The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin-proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues.
View Article and Find Full Text PDFJ Nat Prod
January 2025
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.
Cannabidiol (CBD) is a natural product associated with a wide range of biological and therapeutic activities. Despite the widespread cultural acceptance of CBD as a medicinal agent, much remains to be determined regarding its precise mechanism(s) of action in treating multiple conditions. CBD has been shown to promiscuously interact with several neurological targets with varying affinities.
View Article and Find Full Text PDFAnnu Rev Pathol
January 2025
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA; email:
Over the last two decades, there have been extensive efforts to develop small-molecule inhibitors of protein-protein interactions (PPIs) as novel therapeutics for cancer, including hematologic malignancies. Despite the numerous challenges associated with developing PPI inhibitors, a significant number of them have advanced to clinical studies in hematologic patients in recent years. The US Food and Drug Administration approval of the very first PPI inhibitor, venetoclax, demonstrated the real clinical value of blocking protein-protein interfaces.
View Article and Find Full Text PDFOrg Lett
January 2025
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
Human African trypanosomiasis (HAT) is one of the most lethal of the neglected tropical diseases. While the discovery of a novel antitrypanosomal drug is highly desired, the creation of a superior lead compound is challenging. Herein we report ukabamide (), which was isolated from a marine sp.
View Article and Find Full Text PDFCancer Rep (Hoboken)
January 2025
Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
Background: The breakthrough discovery of novel biomarkers with prognostic and diagnostic value enables timely medical intervention for the survival of patients diagnosed with gastric cancer (GC). Typically, in studies focused on biomarker analysis, highly connected nodes (hubs) within the protein-protein interaction network (PPIN) are proposed as potential biomarkers. However, this study revealed an unexpected finding following the clustering of network nodes.
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