scholarly journals Discovery and mechanism of action of small molecule inhibitors of ceramidases

2021 ◽  
Author(s):  
Sebastien Granier ◽  
Robert D Healey ◽  
Essa Saied ◽  
Xiaojing Cong ◽  
Gergely Karsai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Integral Membrane Proteins ◽  
Sphingolipid Metabolism ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Sphingosine 1 Phosphate

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes such as energy utilisation and cell proliferation. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to ultimately produce pro-proliferative sphingosine-1-phosphate. Human ceramidases can be soluble proteins (acid and neutral ceramidase) or integral membrane proteins (alkaline ceramidases). Increasing ceramide levels to increase apoptosis has shown efficacy as a cancer treatment using small molecules inhibiting a soluble ceramidase. Due to the transmembrane nature of alkaline ceramidases, no specific small molecule inhibitors have been reported. Here, we report novel fluorescent substrates (FRETceramides) of ceramidases that can be used to monitor enzyme activity in real-time. We use FRETceramides to discover the first drug-like inhibitors of alkaline ceramidase 3 (ACER3) which are active in cell-based assays. Biophysical characterization of enzyme:inhibitor interactions reveal a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules.

scholarly journals Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2071 ◽  
Author(s):  
Katarzyna Guzik ◽  
Marcin Tomala ◽  
Damian Muszak ◽  
Magdalena Konieczny ◽  
Aleksandra Hec ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Production Cost ◽  
Small Molecule Inhibitors ◽  
Clinical Aspects ◽  
New Paradigm ◽  
Promising Alternative ◽  
Clinical Responses ◽  
High Production ◽  
High Production Cost

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.

Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter

2009 ◽  
Vol 451 (3) ◽  
pp. 212-216 ◽  
Author(s):  
Xuan-Chuan Yu ◽  
Wandong Zhang ◽  
Arian Oldham ◽  
Eric Buxton ◽  
Shiv Patel ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
High Affinity
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