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Validation of a novel class of cyclophilin inhibitors for the treatment of non-alcoholic steatohepatitis

Project description

The first oral drug for a common liver disease may be on the horizon

Non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease, refers to inflammation and damage of the liver caused by a build-up of fat. If NASH gets worse, it can cause scarring of the liver and cirrhosis. Weight loss is recommended in cases of obesity, but there are no medicines to treat it. Cyclophilins are a family of proteins that includes cyclophilin D. Inhibitors of cyclophilin D have been implicated as potential therapeutics but selective, oral agents have been elusive. CYPNASH has discovered a new family of small molecules that inhibit cyclophilins. With expertise in business, pharmaceuticals, and basic research, the team plans to streamline discovery and testing of a suitable NASH therapeutic.


Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent chronic liver disease (3-4% of the US population) for which there is currently no approved drug therapy. In the absence of innovative treatments healthcare costs associated with this disease are set to triple over the next decade. To address this unmet medical need, the pharmaceutical industry is currently pursuing a range of liver fibrosis drug discovery programs based on different mode of actions. A compelling mechanism for treating liver damage is pharmacological modulation of the mitochondrial permeability transition pore in liver cells via inhibition of the protein cyclophilin D. However existing cyclophilin inhibitors based on peptidic macrocyclic scaffolds are challenging to optimize into sub-type selective orally bioavailable agents suitable for clinical trials of liver fibrosis.

As part of basic research activities undertaken during ERC StG EBDD to validate a computational-biophysical drug discovery platform, we have discovered a structurally novel family of small molecules that inhibit cyclophilins by targeting a previously unexplored binding pocket. The objective of this POC is to identify a lead compound in this family with potential for development towards a NASH clinical candidate. Such a candidate will form the basis of follow-on lead optimisation programs pursued via partnering or out-licensing with a pharmaceutical partner. The activities of this POC will focus on assembling a data package of in vitro DMPK, in vivo PK, in vitro sub-type selectivity and in vitro and in vivo efficacy measurements in relevant cellular and animal models of liver fibrosis. This POC has been designed in consultation with a major pharmaceutical company and assembles a team of physical and biological scientists and business development executives to maximize the likelihood of delivering a valuable preclinical NASH asset.

Host institution

Net EU contribution
€ 150 000,00
EH8 9YL Edinburgh
United Kingdom

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Scotland Eastern Scotland Edinburgh
Activity type
Higher or Secondary Education Establishments
Total cost
No data

Beneficiaries (1)