Drug Discovery 2022: driving the next life science revolution

Acid ceramidase inhibition as a mechanism to treat lysosomal storage disorders.


M Davies1; R Riseley1; DH Jones1; S Ward1; H Waller-Evans1
1 The Medicines Discovery Institute, Cardiff University, UK


Lysosomal storage disorders (LSDs) are complex metabolic disorders characterised by an abnormal build-up of toxic materials within lysosomes as a result of lysosomal enzyme defects. Due to the complex nature of these disorders, currently, there is no available treatment for the majority of LSDs. Acid ceramidase (ACase), a lipid hydrolase that cleaves ceramide, contributes to the pathology of LSDs by deacylating accumulating glycosphingolipids into lyso-glycosphingolipids, which are potent signalling lipids and are toxic to cells. Therefore, ACase makes a promising therapeutic target as a potential treatment for LSDs.

The cytotoxic chemotherapeutic drug Carmofur is a potent, covalent inhibitor of ACase. However, with the majority of LSD patients being children, Carmofur is unsuitable as a chronic administration treatment for a juvenile population. Additionally, over-inhibition of ACase causes the development of Farber disease, an aggressive LSD. Therefore, our aim is to inhibit ACase enough to alleviate lysosphingolipid-induced pathology, but not enough to induce Farber disease. We aim to do this by developing a non-covalent inhibitor of ACase.

After establishing a fluorescence-based assay to measure ACase activity, we tested numerous in‑house compounds for ACase inhibition. Our most promising compound, compound A, inhibits ACase with an IC50 of 1.4 µM. Preliminary work has also shown that compound A is a non-covalent inhibitor of ACase. Further work, including crystallisation of ACase and compound A, will help discover better inhibitors of ACase.

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