Descrizione del progetto
Il primo farmaco orale per una comune malattia del fegato potrebbe essere all’orizzonte
La steatoepatite non alcolica (NASH, Non-Alcoholic SteatoHepatitis), un tipo di malattia del fegato grasso non alcolica, si riferisce all’infiammazione e ai danni al fegato causati da un accumulo di grasso. Se la NASH peggiora, può provocare formazione di cicatrici del fegato e cirrosi. La perdita di peso è raccomandata in caso di obesità, ma non esistono farmaci per curarla. Le ciclofiline sono una famiglia di proteine che comprende la ciclofilina D. Gli inibitori della ciclofilina D sono stati implicati come potenziali terapie, ma gli agenti orali selettivi sono stati elusivi. CYPNASH ha scoperto una nuova famiglia di piccole molecole che inibiscono le ciclofiline. Grazie all’esperienza in affari, prodotti farmaceutici e ricerca di base, il team ha in programma di semplificare la scoperta e il collaudo di una terapia per la NASH adatta.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-POC-LS - ERC Proof of Concept Lump Sum PilotIstituzione ospitante
EH8 9YL Edinburgh
Regno Unito