2. Academic Validation
  3. High-throughput discovery of novel small-molecule inhibitors of acid Ceramidase

High-throughput discovery of novel small-molecule inhibitors of acid Ceramidase

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):343-348. doi: 10.1080/14756366.2022.2150183.
Mazen Aseeri 1,  José Luis Abad 1,  Antonio Delgado 1 2,  Gemma Fabriàs 1 3,  Gemma Triola 1,  Josefina Casas 1 3
Affiliations

Affiliations

  • 1 Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
  • 2 Department of Pharmacology, Toxicology and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
  • 3 Liver and Digestive Diseases Networking Biomedical Research Centre (CIBEREHD), ISCIII, Madrid, Spain.
PMID: 36519337 DOI: 10.1080/14756366.2022.2150183
Abstract

Ceramide has a key role in the regulation of cellular senescence and Apoptosis. As Ceramide levels are lowered by the action of acid Ceramidase (AC), abnormally expressed in various cancers, the identification of AC inhibitors has attracted increasing interest. However, this finding has been mainly hampered by the lack of formats suitable for the screening of large libraries. We have overcome this drawback by adapting a fluorogenic assay to a 384-well plate format. The performance of this optimised platform has been proven by the screening a library of 4100 compounds. Our results show that the miniaturised platform is well suited for screening purposes and it led to the identification of several hits, that belong to different chemical classes and display potency ranges of 2-25 µM. The inhibitors also show selectivity over neutral Ceramidase and retain activity in cells and can therefore serve as a basis for further chemical optimisation.

Keywords

Sphingolipids; acid ceramidase; ceramide; inhibitor.

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