SCIENTIFIC EXPERTISE AND STRATEGY: NUCLEAR RECEPTORS AND MULTIFACTORIAL DISEASES
Genfit's scientific expertise originates from a comprehensive knowledge of gene regulation, which is used in our drug discovery strategy to modulate gene expression by acting on specific transcription factors. By focusing on the family of transcription factors known as “Nuclear Receptors” Genfit is developing the next generation of medicines, and has established innovative strategies for generating drug candidates with desirable “efficacy/safety” profiles for the prevention and treatment of multifactorial cardiometabolic and neurodegenerative diseases. In particular, Genfit is focused on the unmet medical needs in type 2 diabetes, where the pluripotent activities of nuclear receptors are well suited to address the multiple disorders that frequently coexist in pre-diabetic and diabetic patients.
KEY BIOLOGICAL PROCESSES ARE CONTROLLED BY GENE REGULATION
The biological functions of cells and tissues are controlled by gene expression, which is regulated by certain proteins called transcription factors. Depending on the activity of transcription factors, genes will be switched on or off. Among the transcription factors, nuclear receptors are a family involved in the regulation of key biological processes.
The modes of action of transcription factors is continuously studied by the world's scientific community, and recently novel mechanisms have been proposed and demonstrated (simplified schematic shown below). The modulation of gene expression by a nuclear receptor is dependent on its interaction with specific protein “cofactors” in a multiprotein complex. The composition of the multiprotein complex dictates gene regulation in a cell type-dependent manner. Genfit has developed expertise in understanding this complex mechanism and process, and has translated it into screening strategies for selecting the most promising compounds.
NUCLEAR RECEPTORS ARE RELEVANT DRUG TARGETS FOR CARDIOMETABOLIC AND NEURODEGENERATIVE DISEASES
Transcription factors, particularly nuclear receptors, represent attractive therapeutic targets because they provide an approach for modulating biological activities, and hence, improve physiological states appropriate for the patient's treatment. Nuclear receptors have a particular advantage because they are regulated by the binding of specific ligands, which can lead to increased or decreased target gene expression.
In fact, the regulation of nuclear receptor activity is the central mechanism of action of several current drugs on the market (estrogens, glucocorticoids, androgens, fibrates, etc.), accounting for over ten percent of the world's 100 best selling drug products.
The ability of nuclear receptors to regulate multiple genes makes them ideal therapeutic targets for the prevention and/or treatment of multifactorial diseases such as, metabolic and neurodegenerative diseases. For example, patients with type 2 diabetes frequently have multiple disorders which can include dyslipidemia, a pro-inflammatory state, and insulin resistance. Therefore, targeting a nuclear receptor that can address both “insulin resistance and inflammation” or “dyslipidemia and inflammation” would have clear advantages over a therapeutic target with a single physiological effect. Additionally, the development of drugs which can target more than a single nuclear receptor would represent further advantages. Peroxisome Proliferator-Activated Receptor (PPAR) subtypes, α, β and γ are examples of such nuclear receptors which hold great promise for treating various metabolic disorders.
Genfit is currently developing a new generation of safer medicines that target nuclear receptors. Genfit’s approach to profile nuclear receptor ligands, using a comprehensive panel of in vitro and in vivo assays, enables our scientists to identify Selective Nuclear Receptor Modulators (SNuRMs), which demonstrate positive pharmacological effects over unwanted side-effects. Genfit’s differential cofactor recruitment technology is an alternative approach to identify active ligands, that can also differentiate between lead compounds to help identify those with a potential competitive advantage. The technology is based on the ability of different nuclear receptor ligands to induce differential cofactor recruitment and subsequently regulate a subset of target genes (illustrated below).
It is in this context that Genfit is engaged in drug discovery programs targeting several nuclear receptors which have the potential to generate first-in-class SNuRM drug candidates.
