OUR SCIENTIFIC EXPERTISE AND STRATEGY: THE SNuRM REVOLUTION
Genfit's scientific expertise originates from a long-standing knowledge of gene regulation. Small molecules may be selected as drug candidates based on their capacity to modulate gene expression, via their action on specific transcription factors. Genfit has addionally gained solid experience in the family of transcription factors known as 'Nuclear Receptors', and has developed innovative strategies for selecting drug candidates with the best 'efficacy/safety' ratio, i.e. using Selective Nuclear Receptor Modulation approaches ('SNuRM').
HOW KEY BIOLOGICAL PROCESSES ARE CONTROLLED BY GENE REGULATION
In cells, gene expression controls tissue functionality and operates through certain regulatory elements (proteins called transcription factors). Depending how these regulatory elements are activated, genes will be switched on and others switched off. These transcription factors represent attractive therapeutic targets for researchers because they make it possible to modulate a physiological activity that is impaired in a given disease, and to restore it in conditions appropriate for the patient's treatment.
The mode of action of transcription factors has been further explored by the world's scientific community in recent years, and revealed it to be more complex as illustrated below. Additionally, from the 'molecule-transcription factor-gene' binding group, a complex of several 'cofactors' is implicated. Genfit has specifically developed expertise in understanding this complexity, and translating it into screening strategies for selecting the best compounds.
WHY ARE NUCLEAR RECEPTORS RELEVANT DRUG TARGETS ?
Nuclear receptors form a specific family of transcription factors involved in the regulation of many physiological processes. The activation or inactivation of nuclear receptors is one of the central mechanisms of action of many current drugs (Estrogen, glucocorticoid, androgen, steroids, PPAR...): Over ten percent of the world's 100 best selling drugs are targeting nuclear receptors.
As an example, peroxisome proliferator-activated receptor (PPAR) sub-types, including PPAR-α, -γ or -δ, show great promise for treating various metabolic diseases, as they control the transcription of genes involved in glucose metabolism, lipid metabolism and inflammation. Professors Fruchart and Staels were among the first to prove that these ligand-activated transcription factors regulate a wide range of biological processes, in particular the control of lipid and glucose metabolism.
HOW THE SNuRM CONCEPT BRINGS ADDED VALUE FOR DRUG DISCOVERY
Genfit is currently developing a new generation of safer medicines targeting nuclear receptors: Selective Nuclear Receptor Modulators. SNuRMs are nuclear receptor ligands having cell or tissue specific activities, which have been carefully selected as compounds with an optimum efficacy/safety ratio. The SNuRM approach, illustrated below, via Genfit’s cofactor recruitment profiling platform, enables us to develop selective compounds for nuclear receptors which have a competitive advantage for drug discovery programmes.
We have obtained proof-of-concept that the analysis of differential co-factor recruitment can help choose the right compounds which favour pharmacological effects over unwanted side-effects. In this context, Genfit has a number of ongoing nuclear receptor programs including LXR, FXR and PPAR, which may have the desired profiles to be first-in-class SNuRM drug candidates.
